Syn-isomer of 3,7-disubstituted-3-cephem-4-carboxylic acid compounds and processes for the preparation thereof

ABSTRACT

Cephalosporin intermediates have been synthesized.

This is a division of application Ser. No. 767,700, filed Feb. 11, 1977now U.S. Pat. No. 4,166,115.

Other related cases are Ser. Nos. 877,848 and 941,541 filed Feb. 15 andSept. 12, 1978, both of which are continuation-in-parts of Ser. No.767,700. Ser. No. 941,541 was abandoned after filing acontinuation-in-part thereto, Ser. No. 077,557 on Sept. 21, 1979.

The present invention relates to new syn-isomer of3,7-disubstituted-3-cephem-4-carboxylic acid compounds andpharmaceutically acceptable salts thereof. More particularly, it relatesto new syn-isomer of 3,7-disubstituted-3-cephem-4-carboxylic acidcompounds and pharmaceutically acceptable salts thereof which haveantibacterial activities and to processes for the preparation thereof,to pharmaceutical composition comprising the same, and to a method ofusing the same therapeutically in the treatment of infectious diseasesin human being and animals.

Accordingly, it is one object of the present invention to providesyn-isomer of 3,7-disubstituted-3-cephem-4-carboxylic acid compounds andpharmaceutically acceptable salts thereof, which are highly activeagainst a number of pathogenic bacteria.

Another object of the present invention is to provide processes for thepreparation of syn-isomer of 3,7-disubstituted-3-cephem-4-carboxylicacid compounds and pharmaceutically acceptable salts thereof.

A further object of the present invention is to provide pharmaceuticalcomposition comprising, as active ingredients, said syn-isomer of3,7-disubstituted-3-cephem-4-carboxylic acid compounds andpharmaceutically acceptable salts thereof.

Still further object of the present invention is to provide a method forthe treatment of infectious diseases caused by pathogenic bacteria inhuman being and animals.

The object syn-isomer of 3,7-disubstituted-3-cephem-4-carboxylic acidcompounds are novel and can be represented by the following formula (I):##STR1## in which R¹ is a group of the formula: ##STR2## wherein R⁵ ishydrogen, halogen, nitro, hydroxy, lower alkoxy or acyloxy and R⁶ ishydroxy, lower alkoxy, acyloxy, acylamino or di(lower)alkylamino;

a group of the formula: ##STR3## wherein R⁷ is amino, protected amino,hydroxy or lower alkyl; or a group of the formula: ##STR4## wherein R⁸is lower alkyl and R⁹ is imino, protected imino or oxo;

R² is an aliphatic hydrocarbon group which may have suitablesubstituent(s);

R³ is carboxy or protected carboxy; and

R⁴ is acyloxymethyl, hydroxymethyl, formyl or a heterocyclicthiomethylgroup which may have suitable substituent(s);

or R³ and R⁴ are linked together to form --COOCH₂ --.

With regard to the present invention, it is to be noted that thisinvention is characterized by providing syn-isomer of3,7-disubstituted-3-cephem-4-carboxylic acid compounds, which isrepresented by the formula (I), and the said syn-isomer can berepresented by the partial structure of the formula: ##STR5## in theirmolecules, while the corresponding anti-isomer is represented by thepartial structure of the formula: ##STR6## Accordingly, in the followingdetailed explanations of this invention in this specification andclaims, it is to be understood that the syn-isomers of the objectcompounds as well as the starting compounds of this invention arerepresented by the partial structure of the formula: ##STR7## in theirmolecules, provided that, in case that it is convenient for theexplanation of this invention to express both of the syn-isomer andanti-isomer by one general formula, they are represented by the partialstructure of the formula: ##STR8##

The object compounds of the present invention (I) are novel compoundsand can be prepared by the Processes 1 to 8 as mentioned below. ##STR9##wherein R¹, R², R³, R⁴ and R⁵ are each as defined above;

R^(1a) is a group of the formula: ##STR10## in which R^(7a) is protectedamino; or a group of the formula ##STR11## in which R⁸ is as definedabove and R^(9a) is protected imino; R^(1b) is a group of the formula:##STR12## or a group of the formula: ##STR13## in which R⁸ is as definedabove; R^(5a) is hydrogen, halogen, nitro, lower alkoxy or acyloxy;

R^(6a) is acyloxy;

R^(2a) is protected carboxy(lower)alkyl;

R^(2b) is carboxy(lower)alkyl; R^(4a) is a protective group of amino;

R^(4b) is a group which can be substituted by a group R^(4c) --S--wherein R^(4c) is a heterocylic group which may have suitablesubstituent(s); and

R^(4c) is as defined above.

Among the starting compounds, the starting compound (III), including thecorresponding anti-isomer are novel and can be prepared by the processeswhich are illustrated by the following scheme. ##STR14## in which R²,R⁵, R⁶, R^(5a), R^(6a), R^(7a), R⁸ and R^(9a) are each as defined above;

R^(5b) is halogen;

Y is an acid residue;

R¹⁰ is ar(lower)alkyl;

R^(5c) is hydrogen, halogen or nitro;

R^(6b) is lower alkoxy, ar(lower)alkoxy or acylamino;

R^(2c) is hydrogen, lower alkyl or lower alkenyl;

R^(5d) is hydrogen, halogen, nitro, hydroxy or lower alkoxy;

X is halogen;

Z is protected carboxy;

R^(7b) is lower alkyl, amino or lower alkoxy;

R^(7c) is lower alkyl, amino or hydroxy;

R^(7d) is lower alkyl;

R^(2e) is lower alkyl;

R^(1c) is a group of the formula: ##STR15## in which R⁷ is as definedabove, or a group of the formula: ##STR16## in which R⁸ and R⁹ are eachas defined above; R^(2d) is lower alkyl or lower alkenyl; and

Z_(a) is carboxy or protected carboxy.

The other starting compounds (IV), (V), (V_(a))-(V_(c)) and (V_(e)) areall novel compounds and can be prepared by the aforesaid Processes 1 to8.

Regarding the object compounds of the formulae (I), (I_(a)) and(I_(c))-(I_(g)), and the starting compounds of the formulae (III),(III_(e)), (III_(f)), (III_(h)), (IV), (V_(a))-(V_(c)), (V_(e)),(XXIII)-(XXIII_(b)), (XXIX)-(XXXVII) and (XXXIX), it is to be understoodthat said object and starting compounds include tautomeric isomersrelating to their thiazole groups. That is, in case that the grouprepresented by the formula: ##STR17## (wherein R^(7e) is amino,protected amino or hydroxy) in the formula of said object and startingcompounds take the formula: ##STR18## (R^(7e) is as defined above), saidgroup of the formula: ##STR19## can be also alternatively represented byits tautomeric formula: ##STR20## (wherein R^(7f) is imino, protectedimino or oxo). That is, both of the said groups (A) and (B) are in thestate of equilibrium as so-colled tautomeric forms which can berepresented by the following equilibrium: ##STR21## (wherein R^(7e) andR^(7f) are each as defined above).

These types of tautomerism between 2-amino- and 2-hydroxythiazolecompounds and 2-imino-or 2-oxo-thiazoline compounds as stated above havebeen well known in the literature, and it is obvious to a person skilledin arts that both of the tautomeric isomers are equilibrated and easilyconvertible reciprocally, and accordingly it is to be understood thatsuch isomers are included within the same category of the compound perse. Accordingly, the both of the tautomeric forms of the objectcompounds (I), (I_(a)) and (I_(c))-(I_(g)), and the starting compounds(III), (III_(e)), (III_(f)), (III_(h)), (IV), (V_(a))-(V_(c)), (V_(e)),(XXIII)-(XXIII_(b)), (XXIX)-(XXXVII) and (XXXIX) are clearly includedwithin the scope of the present invention. In the present specification,claims and examples, the object and starting compounds including thegroup of such tautomeric isomers are represented by using one of theexpressions therefor, that is the formula: ##STR22## only for theconvenient sake.

Furthermore, regarding the object compounds (I), (I_(a))-(I_(c)) and(I_(g)), and the starting compounds (II), (IV), (V) and (V_(a)), thecompounds wherein R³ is carboxy and R⁴ is formyl can be also regarded assubstantially same compounds as the compounds wherein R³ and R⁴ arelinked together to form a group of the formula: --COOCH(OH)--, i.e.so-called intramolecular hemiacylal type compounds, and accordingly bothof them are understood to be included within the same category of thecompound per se and therefore within the scope of the present invention.

Suitable pharmaceutically acceptable salt of the object syn-isomer of3,7-disubstituted-3-cephem-4-carboxylic acid compounds (I) areconventional non-toxic salts and may include an inorganic salt, forexample, a metal salt such as an alkali metal salt (e.g., sodium salt,potassium salt, etc.) and an alkaline earth metal salt (e.g., calciumsalt, magnesium salt, etc.), ammonium salt etc., an organic salt, forexample, an organic amine salt (e.g., trimethylamine salt, triethylaminesalt, ethanolamine salt, diethanolamine salt, pyridine salt, picolinesalt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.)etc., an organic acid salt (e.g., acetate, maleate, tartrate,methanesulfonate, benzenesulfonate, toluenesulfonate, etc.), aninorganic acid salt (e.g., hydrochloride, hydrobromide, sulfate,phosphate, etc.), or a salt with an amino acid (e.g., arginine, asparticacid, glutamic acid, etc.), and the like.

In the above and subsequent descriptions of the present specification,suitable examples and illustrations of the various definitions which thepresent invention intend to include within the scope thereof areexplained in details as follows.

The term "lower" is intended to mean 1 to 6 carbon atom(s), unlessotherwise provided.

Aliphatic hydrocarbon group is intended to mean straight or branchedaliphatic hydrocarbon having 1 to 6 carbon atom(s) and may include loweralkyl, lower alkenyl and the like. And said aliphatic hydrocarbon groupmay have 1 to 2 suitable substituent(s) such as carboxy, protectedcarboxy, arylthio, lower alkylthio, aryl, acyloxy, lower alkoxy,aryloxy, a heterocyclic group or the like.

Suitable halogen may include chlorine, bromine, fluorine and iodine.

Suitable lower alkoxy and lower alkoxy moiety in the term"ar(lower)alkoxy" may include one which may be branched, for example,methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy,pentyloxy, hexyloxy and the like, and preferably one having 1 to 4carbon atom(s), and more preferably one having 1 to 2 carbon atom(s).

Suitable protected amino may include an acylamino and amino groupsubstituted by a conventional protective group other than the acyl groupsuch as benzyl or the like.

Suitable lower alkyl and lower alkyl moiety in the terms "loweralkylthio", "carboxy(lower)alkyl", "protected carboxy(lower)alkyl","ar(lower)alkyl" and "di(lower)alkylamino" may include one which may bebranched, for example, methyl, ethyl, propyl, isopropyl, butyl,isobutyl, tert-butyl, pentyl, hexyl and the like, and preferably onehaving 1 to 4 carbon atom(s), and more preferably one having 1 to 4carbon atom(s).

Suitable protected imino may include an acylimino and imino groupsubstituted by a conventional protective group other than the acyl groupsuch as benzyl and the like.

Suitable protected carboxy and protected carboxy moiety in the term"protected carboxy(lower)alkyl" may include esterified carboxy in whichsaid ester may be the ones such as lower alkyl ester (e.g., methylester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutylester, t-butyl ester, pentyl ester, t-pentyl ester, hexyl ester,1-cyclopropylethyl ester, etc.), wherein lower alkyl moiety may bepreferably one having 1 to 4 carbon atom(s); lower alkenyl ester (e.g.,vinyl ester, allyl ester etc.); lower alkynyl ester (e.g., ethynylester, propynyl ester, etc.); mono(or di or tri)-halo(lower)alkyl ester(e.g., 2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc.);

lower alkanoyloxy(lower)alkyl ester (e.g., acetoxymethyl ester,propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethylester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, 2-acetoxyethylester, 2-propionyloxyethyl ester, etc.); loweralkanesulfonyl(lower)alkyl ester (e.g., mesylmethyl ester, 2-mesylethylester etc.);

ar(lower)alkyl ester, for example, phenyl(lower)alkyl ester which mayhave one or more suitable substituent(s) (e.g., benzyl ester,4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, tritylester, diphenylmethyl ester, bis(methoxyphenyl)methyl ester,3,4-dimethoxybenzyl ester, 4-hydroxy-3,5-ditertiarybutylbenzyl ester,etc.);

aryl ester which may have one or more suitable substituent(s) (e.g.,phenyl ester, tolyl ester, tertiarybutylphenyl ester, xylyl ester,mesityl ester, cumenyl ester, etc.), and the like. Preferable example ofprotected carboxy may be lower alkoxycarbonyl (e.g., methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl,t-pentyloxycarbonyl, hexyloxycarbonyl, etc.) having 2 to 7 carbon atoms,preferably one having 2 to 5 carbon atoms.

Suitable aryl and aryl moiety in the terms "ar(lower)alkyl","ar(lower)alkoxy", "arylthio" and "aryloxy" may include phenyl, tolyl,xylyl, mesityl, cumenyl, naphthyl and the like, wherein said aryl groupmay have 1 to 3 suitable substituent(s) such as halogen (e.g., chlorine,bromine, iodine or fluorine), hydroxy, and the like.

Suitable heterocyclic group and heterocyclic moiety in the term "aheterocyclicthiomethyl group which may have suitable substituent(s)"means saturated or unsaturated, monocyclic or polycyclic heterocyclicgroup containing at least one hetero-atom such as an oxygen, sulfur,nitrogen atom and the like.

And, especially preferable heterocyclic group may be heterocyclic groupsuch as

unsaturated 3 to 8-membered (preferably 5 to 6 membered)heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example,pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide,pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl,1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl (e.g.,1H-tetrazolyl, 2H-tetrazolyl, etc.), etc; saturated 3 to 8-membered(preferably 5 to 6 membered) heteromonocyclic group containing 1 to 4nitrogen atom(s), for example, pyrrolidinyl, imidazolidinyl, piperidino,piperazinyl, etc.; unsaturated condensed heterocyclic group containing 1to 4 nitrogen atom(s), for example, indolyl, isoindolyl, indolizinyl,benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, etc.;

unsaturated 3-to 8-membered (preferably 5 to 6 membered)heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3nitrogen atom(s), for example, oxazolyl, isoxazolyl, oxadiazolyl, (e.g.,1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.) etc.;

saturated 3 to 8-membered (preferably 5 to 6 membered) heteromonocyclicgroup containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), forexample, morpholinyl, etc.; unsaturated condensed heterocyclic groupcontaining 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), forexample, benzoxazolyl, benzoxadiazolyl, etc.;

unsaturated 3 to 8-membered (preferably 5 to 6 membered)heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3nitrogen atom(s), for example, thiazolyl, thiadiazolyl (e.g.,1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.), etc;

saturated 3 to 8-membered (preferably 5 to 6 membered) heteromonocyclicgroup containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), forexample, thiazolidinyl, etc.; unsaturated 3 to 8 membered (preferably 5to 6 membered) heteromonocyclic group containing a sulfur atom, forexample, thienyl, etc.;

unsaturated condensed heterocyclic group containing 1 to 2 sulfuratom(s) and 1 to 3 nitrogen atom(s), for example, benzothiazolyl,benzothiadiazolyl, etc. and the like; wherein said heterocyclic groupmay have 1 to 2 suitable substituent(s) such as lower alkyl (e.g.,methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, cyclopentyl,hexyl, cyclohexyl, etc.), preferably one having 1 to 4 carbon atom(s);lower alkenyl (e.g., vinyl, allyl, butenyl, etc.);

aryl (e.g., phenyl, tolyl, etc.); halogen (e.g., chlorine, bromine,iodine or fluorine); amino; di(lower)alkylamino(lower)alkyl (e.g.dimethylaminomethyl, dimethylaminoethyl, diethylaminopropyl,diethylaminobutyl, etc.), preferably one having 3 to 6 carbon atoms; orthe like.

Suitable lower alkenyl is one having 2 to 6 carbon atoms and mayinclude, for example, vinyl, allyl, isopropenyl, 1-propenyl, 2-butenyl,3-pentenyl and the like, and preferably one having 2 to 4 carbon atoms.

Suitable acyl moiety in the terms "acylamino", "acylimino", "acyloxy"and "acyloxymethyl" as mentioned above may include carbamoyl, aliphaticacyl group and acyl group containing an aromatic or heterocyclic ring.And, suitable examples of the said acyl may be lower alkanoyl (e.g.,formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl,oxalyl, succinyl, pivaloyl, etc.), preferably one having 1 to 4 carbonatom(s), more preferably one having 1 to 2 carbon atom(s); loweralkoxycarbonyl having 2 to 7 carbon atoms (e.g., methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, 1-cyclopropylethoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl,t-pentyloxycarbonyl, hexyloxycarbonyl, etc.), preferably one having 3 to6 carbon atoms;

lower alkanesulfonyl (e.g., mesyl, ethanesulfonyl, propanesulfonyl,isopropanesulfonyl, butanesulfonyl, etc.), preferably one having 1 to 4carbon atom(s), more preferably one having 1 to 2 carbon atom(s);

arenesulfonyl (e.g., benzenesulfonyl, tosyl, etc.);

aroyl (e.g., benzoyl, toluoyl, naphthoyl, phthaloyl, indancarbonyl,etc.);

ar(lower)alkanoyl (e.g., phenylacetyl, phenylpropionyl, etc.);ar(lower)alkoxycarbonyl (e.g., benzyloxycarbonyl, phenethyloxycarbonyl,etc.); and the like.

The acyl moiety as stated above may have 1 to 3 suitable substituent(s)such as halogen (e.g., chlorine, bromine, iodine or fluorine), hydroxy,cyano, nitro, lower alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy,etc.), lower alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl,etc.), lower alkenyl (e.g., vinyl, allyl etc.), acyl such ashalo(lower)alkanoyl (e.g., chloroacetyl, dichloroacetyl,trichloroacetyl, trifluoroacetyl, etc.), aryl (e.g., phenyl, tolyl,etc.), or the like. Suitable examples of the acyl having saidsubstituent(s) may be mono(or di or tri)halo(lower)alkanoyl (e.g.,trifluoroacetyl, trichloroacetyl, etc.), preferably one having 2 to 4carbon atoms;

mono(or di or tri)halo(lower)alkanoylcarbamoyl (e.g.,trichloroacetylcarbamoyl, etc.), preferably one having 3 to 4 carbonatoms; or the like.

Suitable protective group of amino for R^(4a) may include acyl such ashalo(lower)alkanoyl (e.g., chloroacetyl, dichloroacetyl,trichloroacetyl, trifluoroacetyl, etc.), preferably one having 2 to 3carbon atoms, or the like.

Suitable acid residue may include a residue of an acid such as aninorganic acid (e.g., hydrochloric acid, hydrobromic acid, hydriodicacid, sulfuric acid, etc.) or an organic acid (e.g., methanesulfonicacid, benzenesulfonic acid, p-toluenesulfonic acid, etc.).

Suitable example of a group which can be substituted by a group R^(4c)--S-- may include an acid residue such as halogen, azido or acyloxywherein said halogen and acyl moiety of said acyloxy are the same onesas aforementioned.

Among the suitable examples of each of the groups of the objectcompounds as explained and illustrated above, the prefered examplesthereof are illustrated as follows.

Preferable example of R⁵ may be hydrogen halogen (preferably chlorine)or nitro;

preferable example of R⁶ may be hydroxy, lower alkoxy (preferably C₁-C₄, more preferably C₁ -C₂), acyloxy[preferably lower alkanoyloxy(preferably C₁ -C₄, more preferably C₁ -C₂) or carbamoyloxy], acylamino[preferably lower alkanesulfonylamino (preferably C₁ -C₄, morepreferably (C₁ -C₂)] or di(lower)alkylamino (wherein the alkyl moiety ispreferably C₁ -C₄, more preferably C₁ -C₂);

preferable example of R⁷ may be amino, protected amino such as acylamino[preferably lower alkanesulfonylamino (preferably C₁ -C₄, morepreferably C₁ -C₂), trihalo(lower)alkanoylamino (preferably C₁ -C₄, morepreferably C₁ -C₂) lower alkoxycarbonylamino (preferably C₂ -C₇, morepreferably C₃ -C₆) or lower alkanoylamino (preferably C₁ -C₄, morepreferably C₁ -C₂)], hydroxy or lower alkyl (preferably C₁ -C₄, morepreferably C₁ -C₂);

preferable example of R⁸ is C₁ -C₄ lower alkyl, more preferably C₁ -C₂lower alkyl;

preferable example of R⁹ may be protected imino such as acylimino[preferably lower alkanesulfonylimino (preferably C₁ -C₄, morepreferably C₁ -C₂)];

preferable example of R² may be lower alkyl (preferably C₁ -C₄, morepreferably C₁ -C₂, most preferably C₁), lower alkenyl, ar(lower)alkenyl[more preferably phenyl(lower)alkenyl], carboxy(lower)alkyl, protectedcarboxy(lower)alkyl [more preferably lower alkoxycarbonyl (preferably C₃-C₆) (lower)alkyl], arylthio(lower)alkyl [more preferablyphenylthio(lower)alkyl], ar(lower)alkyl [more preferablyphenyl(lower)alkyl] which may have halogen (preferably bromine) andhydroxy, thienyl(lower)alkyl or aryloxy(lower)alkyl [more preferablyphenoxy(lower)alkyl] which may have hydroxy, in which alkenyl andalkenyl moiety is C₂ -C₆, preferably C₂ -C₄, and alkyl moiety ispreferably C₁ -C₄, more preferably C₁ -C₂ ;

preferable example of R³ may be carboxy;

preferable example of R⁴ may be acyloxymethyl [preferably loweralkanoyloxymethyl (in which alkanoyl moiety is preferably C₁ -C₄, morepreferably C₁ -C₂, most preferably C₂, i.e. acetyl) orcarbamoyloxymethyl which may have trihalo(lower)alkanoyl (in whichtrihalo moiety is preferably trichloro and alkanoyl moiety is preferablyC₂ -C₃ ], hydroxymethyl, formyl, tetrazolylthiomethyl which may havelower alkyl (preferably C₁ -C₄, more preferably C₁ -C₂) ordi(lower)alkylamino(lower)alkyl (in which alkyl moiety is preferably C₁-C₄, more preferably C₁ -C₂), triazolylthiomethyl which may have loweralkyl (preferably C₁ -C₄, more preferably C₁ -C₂) orthiadiazolylthiomethyl which may have lower alkyl (preferably C₁ -C₄,more preferably C₁ -C₂); or R³ and R⁴ are linked together to form--COOCH₂ --.

The various processes for preparing the object compounds of the presentinvention are explained in details in the following.

Process 1

The object compound (I) or a salt thereof can be prepared by reactingthe compound (II) or its reactive derivative at the amino group or asalt thereof with the compound (III) or its reactive derivative at thecarboxy group or a salt thereof, which is a fundamental method forpreparing the object compound (I).

Suitable reactive derivative at the amino group of the compound (II) mayinclude conventional reactive derivative used in amidation, for example,a silyl derivative formed by the reaction of the compound (II) with asilyl compound such as bis(trimethylsilyl)acetamide,trimethylsilylacetamide or the like.

Suitable salt of the compound (II) may include an acid addition saltsuch as an organic acid salt (e.g., acetate, maleate, tartrate,benzenesulfonate, toluenesulfonate, etc.) or an inorganic acid salt(e.g., hydrochloride, hydrobromide, sulfate, phosphate, etc.); a saltwith an inorganic base such as an alkali metal salt (e.g., sodium salt,potassium salt, etc.), an alkaline earth metal salt (e.g., calcium salt,magnesium salt, etc.) or ammonium salt; a salt with an organic base(e.g., triethylamine salt, pyridine salt, etc.); and the like.

Suitable reactive derivative at the carboxy group of the compound (III)may include conventional one used in amidation.

The salts of the compound (III) may be salts with an inorganic base suchas an alkali metal salts (e.g., sodium or potassium salt), or analkaline earth metal salt (e.g., calcium or magnesium salt), a salt withan organic base such as trimethylamine, triethylamine, pyridine, a saltwith an acid (e.g., hydrochloric acid or hydrobromic acid) or the like.

The reaction is usually carried out in a conventional solvent such aswater, acetone, dioxane, acetonitrile, chloroform, methylene chloride,ethylene chloride, tetrahydrofuran, ethyl acetate,N,N-dimethylformamide, pyridine or any other organic solvent which doesnot adversely influence to the reaction. Among these solvent,hydrophilic solvents may be used in a mixture with water.

The present reaction is preferably carried out in the presence of acondensing agent such as so-called Vilsmeier reagent, for example,(chloromethylene) dimethylammonium chloride produced by the reaction ofdimethylformamide with thionyl chloride or phosgene, a compound producedby the reaction of dimethylformamide with phosphorus oxychloride, etc.,or the like.

The reaction may be also carried out in the presence of an inorganic oran organic base such as an alkali metal hydroxide, an alkali metalbicarbonate, alkali metal carbonate, alkali metal acetate,tri(lower)alkylamine, pyridine, N-(lower)alkylmorphorine,N,N-di(lower)alkylbenzylamine, N,N-di(lower)alkylaniline as exemplifiedbelow, or the like. When the base or the condensing agent is in liquid,it can be used also as a solvent. The reaction temperature is notcritical, and the reaction is usually carried out under cooling or atambient temperature.

In the present reaction, it is to be noted that, in case that thestarting compound (III) is reacted with the compound (II) or itsreactive derivative at the amino group or a salt thereof in the presenceof, for example, phosphorus pentachloride, thionyl chloride, etc., onlythe corresponding anti-isomer to the object compound (I) or a mixture ofthe corresponding anti-isomer and syn-isomer is always given as anobject compound even if the compound (III), i.e., syn-isomer is used asa starting compound. It is of course to be noted that the reaction ofthe corresponding anti-isomer to the starting compound (III) with thecompound (II) can never produce the object compound (I) of the presentinvention, i.e. syn-isomer. It may be understood that such tendency andsingularity of the reaction as mentioned above is due to the fact thatthe less stable syn-isomer tends to isomerize partially or wholly to thecorresponding more stable anti-isomer in the course of the reaction, forexample, in so-called activation step of the compound (III) so that theisomerized compound, i.e. the anti-isomer corresponding to the objectcompound (I) can be produced as an object compound.

Accordingly, in order to obtain the object compound (I), i.e.,syn-isomer selectively and in high yield, it is necessary to use thestarting compound (III), i.e., syn-isomer and to select a suitablereaction condition. That is, the object compound (I), i.e., syn-isomercan be obtained selectively and in high yield by conducting thereaction, for example, in the presence of a Vilsmeier reagent asmentioned above etc. and under around neutral condition.

Especially, in case that the starting compound (III) wherein R¹ is agroup of the formula: ##STR23## is used, the object compound (I), i.e.,syn-isomer can be obtained selectively and in high yield by conductingthe present reaction of the corresponding starting compound (III), i.e.,syn-isomer with the compound (II), for example, in the presence of aVilsmeier reagent produced by the reaction of dimethylformamide withphosphorus oxychloride and under around neutral condition. And, in thiscase, it is to be noted that particularly good results can be achievedby conducting the reaction in the presence of more than two molarequivalents of phosphorus oxychloride to each amount of the saidstarting compound (III), i.e., syn-isomer and dimethylformamide as shownin the working examples. Further, in this case, it is to be also notedthat good results can be achieved by conducting an activation step ofthe starting compound (III), i.e., syn-isomer in the presence of a silylcompound [e.g. bis(trimethylsilyl)acetamide, trimethylsilyacetamide,etc.] and the like.

With regard to the reaction of the compound (II) with the compound(III), it is to be noted that;

when the compound (II) wherein R⁴ is carbamoyloxymethyl group havingacyl group is used as a starting compound, there may be obtainedoccasionally either the object compound (I) wherein R⁴ iscarbamoyloxymethyl group having acyl group or free carbamoyloxymethylgroup according to reaction conditions;

when the compound (II) wherein R⁴ is hydroxymethyl group is used as astarting compound, there may be obtained occasionally the objectcompound (I) wherein R³ and R⁴ are linked together to form --COOCH₂ --;

and further the protected carboxy group or salts in the compound (II)may be converted into free carboxy group; in the course of the reactionor in post-treatment. These cases are also included within the scope ofthe present invention.

As clear from the explanation as stated above, it is to be understoodthat the Process 1 is a fundamental and the most advantageous method forpreparing the object compound (I), i.e. syn-isomer.

Process 2

The object compound (I_(a)) or a salt thereof can be prepared bysubjecting the compound (IV) or a salt thereof to elimination reactionof the protective group of the amino or imino.

Suitable salt of the compound (IV) may include a metal salt, ammoniumsalt, an organic amine salt and the like as aforementioned.

The present elimination reaction is carried out in accordance with aconventional method such as hydrolysis; reduction; a method by reactingthe compound (IV) wherein the protective group is acyl group withiminohalogenating agent and then with iminoetherifying agent, and, ifnecessary, subjecting the resulting compound to hydrolysis; or the like.The hydrolysis may include a method using an acid or base or hydrazineand the like. These methods may be selected depending on the kind of theprotective groups to be eliminated.

Among these methods, hydrolysis using an acid is one of the common andpreferable method for eliminating the protective groups such assubstituted or unsubstituted alkoxycarbonyl (e.g., t-pentyloxycarbonyl,etc.), alkanoyl (e.g., formyl, etc.), cycloalkoxycarbonyl, substitutedor unsubstituted aralkoxycarbonyl (e.g., benzyloxycarbonyl, substitutedbenzyloxycarbonyl, etc.), substituted phenylthio, substitutedaralkylidene, substituted alkylidene, substituted cycloalkylidene, orthe like. Suitable acid may include an organic or an inorganic acid, forexample, formic acid, trifluoroacetic acid, benzenesulfonic acid,p-toluenesulfonic acid, hydrochloric acid and the like, and preferableacid is an acid which can be easily removed from the reaction mixture bya conventional manner such as distillation under reduced pressure, forexample, formic acid, trifluoroacetic acid, hydrochloric acid, etc. Theacid suitable for the reaction can be selected according to the kind ofprotective group to be eliminated. When the elimination reaction isconducted with the acid, it can be carried out in the presence orabsence of a solvent. Suitable solvent may include an organic solvent,water or a mixed solvent thereof. When trifluoroacetic acid is used, theelimination reaction may be preferably carried out in the presence ofanisole.

The hydrolysis using hydrazine is commonly applied for eliminating theprotective group, for example, succinyl or phthaloyl.

The hydrolysis with a base is preferably applied for eliminating acylgroup, for example, haloalkanoyl (e.g., trifluoroacetyl, etc.) etc.Suitable base may include, for example, an inorganic base such as alkalimetal hydroxide (e.g., sodium hydroxide, potassium hydroxide, etc.),alkaline earth metal hydroxide (e.g., magnesium hydroxide, calciumhydroxide, etc.), alkali metal carbonate (e.g., sodium carbonate,potassium carbonate, etc.), alkaline earth metal carbonate (e.g.,magnesium carbonate, calcium carbonate, etc.), alkali metal bicarbonate(e.g., sodium bicarbonate, potassium bicarbonate, etc.), alkali metalacetate (e.g., sodium acetate, potassium acetate, etc.), alkaline earthmetal phosphate (e.g., magnesium phosphate, calcium phosphate, etc.),alkali metal hydrogen phosphate (e.g., disodium hydrogen phosphate,dipotassium hydrogen phosphate, etc.), or the like, and an organic basesuch as trialkylamine (e.g., trimethylamine, triethylamine, etc.),picoline, N-methylpyrrolidine, N-methylmorpholine,1,5-diazabicyclo[4,3,0]non-5-ene, 1,4-diazabicyclo[2,2,2]octane,1,5-diazabicyclo[5,4,0]undecene-5 or the like. The hydrolysis using abase is often carried out in water or a hydrophilic organic solvent or amixed solvent thereof.

Among the protective groups, the acyl group can be generally eliminatedby hydrolysis as mentioned above or by the other conventionalhydrolysis. In case that the acyl group is halogensubstituted-alkoxycarbonyl or 8-quinolyloxycarbonyl, they are eliminatedby treating with a heavy metal such as copper, zinc or the like.

The reductive elimination is generally applied for eliminating theprotective group, for example, haloalkoxycarbonyl (e.g.,trichloroethoxycarbonyl etc.), substituted or unsubstitutedaralkoxycarbonyl (e.g., benzyloxycarbonyl, substituted benzyloxycarbonyletc.), 2-pyridylmethoxycarbonyl, etc. Suitable reduction may include,for example, reduction with an alkali metal borohydride (e.g., sodiumborohydride, etc.) and the like.

Suitable iminohalogenating agent used in a method as mentioned above mayinclude phosphorus trichloride, phosphorus pentachloride, phosphorustribromide, phosphorus pentabromide, phosphorus oxychloride, thionylchloride, phosgene and the like. The reaction temperature is notcritical, and the reaction is usually carried out at ambient temperatureor under cooling. Suitable iminoetherifying agent reacted with thusobtained reaction product may include an alcohol, metal alkoxide and thelike. Suitable alcohol may include alkanol (e.g., methanol, ethanol,propanol, isopropanol, butanol, t-butanol, etc.) which may besubstituted with alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy,butoxy, etc.). Suitable metal alkoxide may include alkali metal alkoxide(e.g., sodium alkoxide, potassium alkoxide, etc.), alkaline earth metalalkoxide (e.g., calcium alkoxide, barium alkoxide, etc.) and the like.The reaction temperature is not critical, and the reaction is usuallycarried out under cooling or at ambient temperature.

Thus obtained product is, if necessary, subjected to hydrolysis. Thehydrolysis can be readily carried out by pouring the reaction mixtureobtained above into water, but there may be previously added ahydrophilic solvent (e.g., methanol, ethanol, etc.), a base (e.g.,alkali metal bicarbonate, trialkylamine, etc.) or an acid (e.g., dilutedhydrochloric acid, acetic acid, etc.) to the water.

The reaction temperature is not critical and may be suitably selected inaccordance with the kind of the protective group of the amino group andthe elimination method as mentioned above, and the present reaction ispreferably carried out under a mild condition such as under cooling, atambient temperature or slightly elevated temperature.

The present invention includes, within its scope, the cases that theprotected carboxy is transformed into the free carboxy group; that whenthe compound (IV) wherein R⁴ is carbamoyloxymethyl group having acylgrup is used as the starting compound, there may be obtainedoccasionally either the object compound (I_(a)) wherein R⁴ iscarbamoyloxymethyl group having acyl group or free carbamoyloxymethylgroup according to reaction conditions; and that when the compound (IV)wherein R⁴ is acyloxymethyl group is used as the starting compound,there may be obtained occasionally the object compound (I_(a)) whereinR³ and R⁴ are linked together to form --COOCH₂ -- according to reactionconditions; in the course of the reaction or in post-treatment.

Process 3

The object compound (I_(b)) or a salt thereof can be prepared byacylating the hydroxy group of the compound (V) or a salt thereof.

Suitable salt of the compound (V) can also be referred to the onesexemplified for the compound (IV).

The acylating agent to be used for the present reaction may include analiphatic, aromatic and heterocyclic carboxylic acid, and thecorresponding sulfonic acid and thio acid which have aforesaid acylgroup as their acyl moieties, and reactive derivatives of theabove-mentioned acids. Suitable reactive derivative of theabove-mentioned acids may include an acid halide, an acid anhydride, anactivated amide, an activated ester, and the like. Suitable example maybe an acid chloride; an acid azide; a mixed acid anhydride with an acidsuch as substituted phosphoric acid (e.g., dialkylphosphoric acid,phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid,halogenated phosphoric acid, etc.), dialkylphosphorous acid, sulfurousacid, thiosulfuric acid, sulfuric acid, alkylcarbonic acid, aliphaticcarboxylic acid (e.g., pivalic acid, pentanoic acid, isopentanoic acid,2-ethylbutyric acid or trichloroacetic acid, etc.) or aromaticcarboxylic acid (e.g., benzoic acid, etc.); a symmetrical acidanhydride; an activated amide with imidazole, 4-substituted imidazole,dimethylpyrazole, triazole or tetrazole; or an activated ester [e.g.,cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl ((CH₃)₂ N⁺═CH--) ester, vinyl ester, propargyl ester, p-nitrophenyl ester,2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester,mesyl phenyl ester, phenylazophenyl ester, phenyl thioester,p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester,pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester], oran ester with N,N-dimethylhydroxylamine, 1-hydroxy-2-(1H)-pyridone,N-hydroxysuccinimide, N-hydroxyphthalimide or1-hydroxy-6-chloro-1H-benzotriazole, and the like. These reactivederivatives can be optionally selected from them according to the kindof the acylating agent to be used.

The acylating agent may further include aliphatic, aromatic orheterocyclic isocyanate or isothiocyanate (e.g., methyl isocyanate,phenyl isocyanate, trichloroacetyl isocyanate, methyl isothiocyanate,etc.) and haloformate (e.g., ethyl chloroformate, benzyl chloroformate,etc.). In this case, for example, when trichloroacetyl isocyanate isused as an acylating agent, trichloroacetylcarbamoyl group is introducedas acyl group and said group may be converted to carbamoyl group bytreating with base, and when ethyl chloroformate is used as an acylatingagent, ethoxycarbonyl group is introduced as acyl group.

The present reaction is carried out according to similar reactionconditions to those of aforesaid reaction of the compound (II) with thecompound (III), and is preferably carried out in the presence of a base.In the reaction of the compound (V) with an acylating agent, theprotected carboxy group or salts in the compound (V) may be convertedinto free carboxy group in the course of the reaction or inpost-treatment;

and when the compound (V) wherein R⁴ is carbamoyloxymethyl group havingacyl group is used as the starting compound, there may be obtainedoccasionally either the object compound (I_(b)) wherein R⁴ iscarbamoyloxymethyl group having acyl group or free carbamoyloxymethylgroup according to reaction conditions in the course of the reaction orin post-treatment. These cases are also included in the scope of thepresent invention.

Process 4

The object compound (I_(c)) or a salt thereof can be prepared bysubjecting the compound (V_(a)) or a salt thereof to eliminationreaction of the protective group of the carboxy.

Suitable salt of the compound (V_(a)) can be referred to the onesexemplified for the compound (IV).

The present elimination reaction is carried out in accordance with aconventional method such as hydrolysis or the like. The hydrolysis mayinclude a method using an acid or base and the like. These methods maybe selected depending on kind of the protective groups to be eliminated.

The hydrolysis using an acid is one of the most common and preferablemethods for eliminating the protective groups such asphenyl(lower)alkyl, substituted phenyl(lower)alkyl, lower alkyl,substituted lower alkyl, or the like. Suitable acid may includeinorganic or organic acid, for example, formic acid, trifluoroaceticacid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid,and the like. The present reaction may be carried out in the presence ofanisole. The acid suitable for the reaction can be selected according tothe protective group to be eliminated and other factors. The hydrolysisusing an acid may be carried out in the presence of a solvent, such asan organic solvent, water or a mixed solvent thereof.

The reaction temperature is not critical and may be suitably selected inaccordance with the kind of the protective group and the eliminationmethod, and the present reaction is preferably carried out under a mildcondition such as under cooling, at ambient temperature or slightlywarming.

The present invention includes, within its scope, the cases that theprotected carboxy group for R³ is transformed into the free carboxygroup; that the protected amino group is transformed into the free aminogroup; that the protected imino group is transformed into the free iminogroup; that the acyloxy group is transformed into the hydroxy group;and/or that the carbamoyloxymethyl group having acyl group istransformed into the free carbamoyloxymethyl group; during the reactionor post-treating in the present reaction.

Process 5

The object compound (I_(d)) or a salt thereof can be prepared bysubjecting the compound (V_(b)) or a salt thereof to eliminationreaction of the protective group of the amino.

Suitable salt of the compound (V_(b)) can be referred to the onesexemplified for the compound (IV).

The present elimination reaction may include an elimination method usinga base, for example, an inorganic base such as an alkali metal hydroxide(e.g., sodium hydroxide, potassium hydroxide, etc.), an alkali metalbicarbonate (e.g., sodium bicarbonate, potassium bicarbonate, etc.) oralkali metal carbonate (e.g., sodium carbonate, potassium carbonate,etc.), an organic base such as an alkali metal alkoxide (e.g., sodiummethoxide, sodium ethoxide, etc.), a trialkylamine (e.g.,trimethylamine, triethylamine, etc.), triethanolamine,N,N-dimethylaniline, N,N-dimethylbenzylamine, N-methylmorpholine orpyridine; and an elimination reaction using basic alumina, basic ionexchange resin, acid (e.g., trifluoroacetic acid, trifluoroacetic acidanisole, etc.). The present elimination reaction is usually carried outin water, hydrophilic solvent or a mixture thereof. The reactiontemperature is not critical and the reaction is preferably carried outat ambient temperature or under cooling.

The present invention includes, within its scope, the cases that theprotected carboxy group or salts in the compound (V_(b)) may beconverted into free carboxy group, and that the protected amino and/orimino group may be converted into the free amino and/or imino group,respectively in the course of the reaction or in post-treatment.

Process 6

The object compound (I_(e)) or a salt thereof can be prepared byreacting the compound (V_(c)) or a salt thereof with the compound(V_(d)) or its reactive derivative at the mercapto group.

Suitable salt of the compound (V_(c)) can be referred to the onesexemplified for the compound (IV).

The suitable reactive derivative at the mercapto group of the compound(V_(d)) may include a metal salt such as alkali metal salts (e.g.,sodium salt, potassium salt, etc.) or the like.

The present reaction may be carried out in a solvent such as water,acetone, chloroform, nitrobenzene, methylene chloride, ethylenechloride, dimethylformamide, methanol, ethanol, ether, tetrahydrofuran,dimethylsulfoxide, or any other solvent which does not adversely affectthe reaction, preferably in ones having strong polarities. Among thesolvents, hydrophilic solvents may be used in a mixture with water. Thereaction is preferably carried out in weekly basic or around neutralcondition. When the compound (V_(c)) and or the thiol compound (V_(d))is used in a free form, the reaction is preferably conducted in thepresence of a base, for example, inorganic base such as alkali metalhydroxide, alkali metal carbonate, alkali metal bicarbonate, organicbase such as trialkylamine, pyridine, and the like. The reactiontemperature is not critical, and the reaction is usually carried out atambient temperature or under warming. The reaction product can beisolated from the reaction mixture by conventional methods.

The reaction of the compound (V_(c)) with the compound (V_(d)) includes,within its scope, the cases that the protected carboxy group or salts inthe compound (V_(c)) may be converted into free carboxy group; that theprotected amino and/or imino group may be converted into free aminoand/or imino group; and that the acyloxy group may be converted intohydroxy group; respectively in the course of the reaction or inpost-treatment.

Process 7

The object compound (I_(f)) or a salt thereof can be prepared bytreating the compound (V_(e)) or a salt thereof with an acid.

Suitable salt of the compound (V_(e)) can be referred to the onesexemplified for the compound (IV).

Suitable acid to be used in the present reaction may include aninorganic acid (e.g., hydrochloric acid, hydrobromic acid, sulfuricacid, etc.) or an organic acid (e.g., formic acid, acetic acid, etc.).

The present reaction is usually carried out in a solvent such as water,acetone, acetic acid or any other solvent which does not adverselyinfluence the reaction. Among these solvents hydrophilic solvents can beused as a mixture with water.

The reaction temperature is not critical and the reaction is preferablycarried out under cooling to warming.

Process 8

The object compound (I_(g)) or a salt thereof can be prepared byoxidizing the compound (V_(e)) or a salt thereof.

Suitable oxidizing agent used in the present reaction may include Jonesreagent being used by a combination of sulfuric acid and chromiumtrioxide, manganese dioxide, a reagent being used by a combination ofdimethylsulfoxide and N,N'-dicyclohexylcarbodiimide etc., and the like.

The present reaction is usually carried out in a solvent such as water,acetone, dimethylformamide or any other solvent which does not adverselyaffect the reaction. These solvents may be used as a mixture thereof.

The reaction temperature is not critical and the reaction is preferablycarried out under cooling or around ambient temperature.

Processes for preparing the starting compound (III) i.e., syn-isomer andanti-isomer thereof used for References are explained in details asfollows.

(A) Process of (VI)+(VII)→(VIII) [Scheme (1)(i)]

The compound (VIII) can be prepared by reacting the compound (VI) withthe compound (VII).

The present reaction is usually carried out in a solvent such as water,ethanol, acetone, ether, dimethylformamide or any other solvent whichdoes not adversely influence the present reaction. The reaction ispreferably carried out in the presence of a base such as an inorganicbase or an organic base as aforementioned. The reaction temperature isnot critical and the reaction is usually carried out under cooling tounder heating of boiling point of the solvent.

(B) Processes of (IX)→(X) [Scheme (1)(ii)] and (XXXII)→(XXXIII) [Scheme(6)(ii)]

The compounds (X) and (XXXIII) can be prepared by oxidizing thecompounds (IX) and (XXXII), respectively.

The present oxidation reaction is conducted by a conventional methodwhich is applied for the transformation of so-called activated methylenegroup into carbonyl group. That is, the present oxidation is conductedby a conventional method such as oxidation by using a conventionaloxidizing agent such as selenium dioxide, potassium permanganate or thelike. The present oxidation is usually carried out in a solvent whichdoes not adversely influence the reaction, for example, water, dioxane,pyridine, tetrahydrofuran, and the like.

The reaction temperature is not critical and the reaction is preferablycarried out under warming to heating.

(C) Process of (XI)→(XII) [Scheme (1) (iii)]

The compound (XII) can be prepared by subjecting the compound (XI) toelimination reaction of the ar(lower)alkyl group.

The present elimination method may include all conventional methods usedin the elimination reaction of the ar(lower)alkyl group, for example,hydrolysis, reduction, etc.

The hydrolysis using acid is one of the most preferable method and theacid to be used may include an inorganic acid (e.g., hydrochloric acid,hydrobromic acid, etc.), an organic acid (e.g., formic acid, aceticacid, trifluoroacetic acid, etc.) and a mixture thereof. The presentreaction can be carried out in a solvent such as water, an organicsolvent or a mixture thereof or without solvent. The reactiontemperature is not critical and the reaction is preferably carried outunder warming to heating.

(D) Processes of (XIII)+(XIV)→(IIIa) [Scheme (1) (iv)],(XXXIII)+(XIV)→(XXXV) [Scheme (6) (ii)] and (XXXIV)+(XIV)→(III_(f))[Scheme (6) (ii)]

The compounds (III_(a)), (XXXV) and (III_(f)) can be prepared byreacting the compounds (XIII), (XXXIII) and (XXXIV) with the compound(XIV) or a salt thereof, respectively.

Suitable salt of the compound (XIV) may include an inorganic acid salt(e.g., hydrochloride, hydrobromide, sulfate, etc.), an organic acid salt(e.g., acetate, p-toluenesulfonate, etc.) and the like.

The present reaction is usually carried out in a solvent such as water,an alcohol (e.g., methanol, ethanol, etc.), a mixture thereof or anyother solvent which does not adversely influence the present reaction.

The present reaction, in case that the compound (XIV) is used in itssalt form, is preferably carried out in the presence of a base, forexample, an inorganic base such as alkali metal (e.g., sodium,potassium, etc.), alkaline earth metal (e.g., magnesium, calcium, etc.),the hydroxide or carbonate or bicarbonate thereof or the like, and anorganic base such as alkali metal alkoxide (e.g., sodium methoxide,sodium ethoxide, etc.), trialkylamine (e.g., trimethylamine,triethylamine, etc.), N,N-dialkylamine (e.g., N,N-dimethylaniline,etc.), N,N-dialkylbenzylamine (e.g., N,N-dimethylbenzylamine, etc.),pyridine or the like.

The reaction temperature is not critical and the reaction is usuallycarried out under cooling to heating.

In the present reaction, the mixture of syn- and anti-isomers of thecompound (III_(a)), (XXXV) or (III_(f)) may be obtained according toreaction conditions etc., and in such case, both isomers may be resolvedby conventional manners from the mixture. For example, the mixture isfirstly esterified and the resulting esters are resolved, for example,by chromatography into each isomer. The resolved each isomer of estersis hydrolyzed by a conventional method to give the corresponding syn- oranti-carboxylic acid.

In order to obtain syn-isomer of the compound (III_(a)), (XXXV) or(III_(f)) selectively and in high yield the present reaction ispreferably carried out around neutral condition.

(E) Processes of (XV)→(XVI) [Scheme (2) (i)] and (XXXIV)→(XXXVI) [Schme(6) (ii)]

The compounds (XVI) and (XXXVI) can be prepared by reacting thecompounds (XV) and (XXXIV) with hydroxylamine or a salt thereof,respectively.

Suitable salt of hydroxylamine can be referred to the ones exemplifiedfor the compound (XIV).

The reaction conditions of the present reaction can also be referred tothe ones exemplified for the processes of (XIII)+(XIV)→(III_(a)),(XXXIII)+(XIV)→(XXXV) and (XXXIV)+(XIV)→(III_(f)) as mentioned inaforementioned (D).

(F) Processes of (XVII)→(XVIII) [Scheme (2) (ii)], (XXIV)→(XXV) [Scheme(4) (ii)](XXVI)→(XXVII) [Scheme (5)] and (XXXVII)→(XXXVIII) [Scheme (6)(iii)]

The compounds (XVIII), (XXV), (XXVII) and (XXXVIII) can be prepared byalkylating the compounds (XVII), (XXIV), (XXVI) and (XXXVII),respectively.

The alkylating agent to be used in the present alkylation reaction mayinclude di(lower)alkyl sulfate (e.g., dimethyl sulfate, diethyl sulfate,etc.), diazo(lower)alkane (e.g., diazomethane, diazoethane, etc.), loweralkyl halide (e.g., methyl iodide, ethyl iodide, etc.), lower alkylsulfonate (e.g., methyl p-toluenesulfonate, etc.), and the like.

The reaction using di(lower)alkyl sulfate, lower alkyl halide or loweralkyl sulfonate is usually carried out in a solvent such as water,acetone, ethanol, ether, dimethylformamide or any other solvent whichdoes not adversely influence the reaction.

The present reaction is preferably carried out in the presence of a basesuch as an inorganic base or an organic base as aforementioned.

The reaction temperature is not critical and the reaction is usuallycarried out under cooling to heating around boiling point of thesolvent.

The reaction using diazoalkane is usually carried out in a solvent suchas ether, tetrahydrofuran or the like.

The reaction temperature is not critical and the reaction is usuallycarried out under cooling or at ambient temperature.

(G) Processes of (XVIII)→(III_(b)) [Scheme (2) (ii)] and(XXXVIII)→(III_(g)) [Scheme (6) (iii)]

The compounds (III_(b)) and (III_(g)) can be prepared by subjecting thecompounds (XVIII) and (XXXVIII) to hydrolysis, respectively.

The hydrolysis is preferably carried out in the presence of a base or anacid. Suitable base may include an inorganic base and an organic basesuch as an alkali metal (e.g., sodium, potassium, etc.), an alkalineearth metal (e.g., magnesium, calcium, etc.), the hydroxide or carbonateor bicarbonate thereof, trialkylamine (e.g., trimethylamine,triethylamine, etc.), picoline, 1,5-diazabicyclo[4,3,0]non-5-ene,1,4-diazabicyclo-[2,2,2]octane, 1,5-diazabicyclo[5,4,0]-undecene-5, orthe like.

Suitable acid may include an organic acid (e.g., formic acid, aceticacid, propionic acid, trifluoroacetic acid, etc.) and an inorganic acid(e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, etc.).

The reaction is usually carried out in a solvent such as water, analcohol (e.g., methanol, ethanol, etc.), a mixture thereof or any othersolvent which does not adversely influence the reaction. A liquid baseor acid can also be used as the solvent.

The reaction temperature is not critical and the reaction is usuallycarried out under cooling to warming.

(H) Process of (XIX)→(III_(c)) [Scheme (3)]

The compound (III_(c)) can be prepared by subjecting the compound (XIX)to acylation.

The acylating agent to be used for the present reaction and the reactionconditions of the present reaction can be referred to the onesexemplified for Process 3.

(I) Process of (XX)→(XXI) [Scheme (4) (i)]

The compound (XXI) can be prepared by subjecting the compound (XX) tonitrosation.

The nitrosating agent to be used for the present reaction may includeconventional agent which give C-nitroso compound by reacting withactivated methylene group, such as nitrous acid, alkali metal nitrite(e.g., sodium nitrite, etc.), lower alkyl nitrite (e.g., isopentylnitrite, t-butyl nitrite, etc.) or the like.

In case that salt of nitrous acid is used as nitrosating agent, thepresent reaction is usually carried out in the presence of an acid suchas an inorganic acid or an organic acid (e.g., hydrochloric acid, aceticacid, etc.). In case that ester of nitrous acid is used, the presentreaction is preferably carried out in the presence of a strong base suchas alkali metal alkoxide or the like.

The present reaction is usually carried out in a solvent such as water,acetic acid, benzene, alcohol (e.g., ethanol, methanol, etc.) or anyother solvent which does not adversely influence the reaction.

The reaction temperature is not critical and the reaction is usuallycarried out under cooling or at ambient temperature.

(J) Processes of (XXI)+(XXII)→(XXIII) [Scheme (4) (i)] and(XXVIII)+(XXII)→(XXIX) [Scheme (5)]

The compounds (XXIII) and (XXIX) can be prepared by reacting thecompounds (XXI) and (XXVIII) with the compound (XXII), respectively.

The present reaction is usually carried out in a solvent such as water,an alcohol (e.g., methanol, ethanol, etc.), benzene, dimethylacetamide,dimethylformamide, tetrahydrofuran, a mixture thereof or any othersolvent which does not adversely influence the reaction.

The reaction temperature is not critical and the reaction is usuallycarried out from ambient temperature to under heating around the boilingpoint of the solvent.

In order to obtain syn-isomer of the compound (XXIII) or (XXIX)selectively and in high yield, it is necessary to use syn-isomer of thestarting compound (XXI) or (XXVIII) and the present reaction ispreferably carried out around neutral condition in the presence of abase as aforementioned. Preferable example of base may be week base suchas alkali metal acetate (e.g., sodium acetate, potassium acetate, etc.),alkali metal bicarbonate (e.g., sodium bicarbonate, potassiumbicarbonate, etc.), alkali metal carbonate (e.g., sodium carbonate,potassium carbonate, etc.) or the like.

(K) Processes of (XXIII)→(XXIII_(a)) [Scheme (4) (i)], (XXV)→(III_(d))[Scheme (4) (ii)], (XXIX)→(III_(e)) [Scheme (5)], (XXXIII)→(XXXIV)[Scheme (6) (ii)] and (XXXV)→(III_(f)) [Scheme (6) (ii)]

The compounds (XXIII_(a)), (III_(d)), (III_(e)), (XXXIV) and (III_(f))can be prepared by subjecting the compounds (XXIII), (XXV), (XXIX),(XXXIII) and (XXXV) to elimination reaction of the protective group ofthe carboxy, respectively.

In the present elimination reaction, conventional methods used in theelimination reaction of the protected carboxy, for example, hydrolysisetc. can be applicable. When the protective group is an ester, it can beeliminated by hydrolysis.

The present hydrolysis is carried out according to similar manners tothose of processes (XVIII)→(III_(b)) and (XXXVIII)→(III_(g)) asmentioned in aforesaid (G).

(L) Process of (XXVII)→(XXVIII) [Scheme (5)]

The compound (XXVIII) can be prepared by halogenating the compound(XXVII).

The halogenating agent to be used in the present reaction may include aconventional halogenating agent used in halogenation of so-calledactivated methylene group such as halogen (e.g., bromine, chlorine,etc.), sulfuryl halide (e.g., sulfuryl chloride, etc.), hypohalite(e.g., hypochlorous acid, hypobromous acid, sodium hypochlorite, etc.),N-halogenated-imide (e.g., N-bromosuccinimide, N-bromophthalimide,N-chlorosuccinimide, etc.) and the like.

The present reaction is usually carried out in a solvent such as anorganic acid (e.g., formic acid, acetic acid, propionic acid, etc.),carbon tetrachloride or any other solvent which does not adverselyinfluence the reaction.

The reaction temperature is not critical and the reaction is usuallycarried out under cooling, at ambient temperature, under warming orheating.

(M) Processes of (XXX)→(XXXI) [Scheme (6) (i)] and (XXXIX)→(III_(h))[Scheme (7)]

The compound (XXXI) can be prepared by reacting the compound (XXX) orits reactive derivative at the amino group or a salt thereof with anamino-protecting agent and the compound (III_(h)) can be prepared byreacting the compound (XXXIX) or its reactive derivative at the aminogroup or a salt thereof with an amino-protecting agent. Suitablereactive derivative at the amino group of the compound (XXX) or (XXXIX)and suitable salt of the compound (XXX) or (XXXIX) may include the sameones as illustrated in the explanations of the reactive derivative atthe amino group of the compound (II) and salt of the compound (II),respectively.

Suitable amino-protecting agent may include acylating agent which mayinclude an aliphatic, aromatic and heterocyclic carboxylic acid, and thecorresponding sulfonic acid, haloformic acid ester, isocyanic acid esterand carbamic acid, and the corresponding thio acid thereof, and thereactive derivative of the above acids.

Suitable reactive derivative of the above acids may include the sameones as illustrated in the explanation of Process 3. The example of theprotective group (e.g. acyl group) to be introduced into the amino groupin the compound (XXX) or (XXXIX) by the above amino-protecting agent(e.g. acylating agent) may be the same protecting group (e.g., acylgroup) as illustrated in the explanation of the protective group moiety(e.g., acyl moiety) in the term "acylamino".

The present amino-protecting reaction is carried out in a similar manneras illustrated in the reaction of the compound (II) with the compound(III) (Process 1).

(N) Process of (XXIII_(b))→(XXXIII) [Scheme (6) (ii)]

The compound (XXXIII) can be prepared by subjecting the compound(XXIII_(b)) to hydrolysis.

The present hydrolysis is carried out in the presence of alkali metalbisulfite (e.g., sodium bisulfite, etc.) titanium trichloride, inorganicor organic acid such as hydrohalogenic acid (e.g., hydrochloric acid,hydrobromic acid, etc.), formic acid, nitrous acid or the like.Hydrohalogenic acid is preferably used in a combination of aldehyde(e.g., formaldehyde, etc.).

The present reaction is usually carried out in a solvent such as water,aqueous alcohol (e.g., aqueous methanol, aqueous ethanol, etc.),water-acetic acid or any other solvent which does not adverselyinfluence the reaction.

The reaction temperature is not critical and the reaction is usuallycarried out at ambient temperature, under warming or heating.

In the present reaction, protected carboxy group may be occasionallytransformed into free carboxy group. This case is also included in thescope of the present invention.

In the aforementioned reactions and/or the post-treating of thereactions of the present invention, the aforementioned tautomericisomers may be occasionally transformed into the other tautomericisomers and such case is also included in the scope of the presentinvention.

In case that the object compound (I) is obtained in a form of the freeacid at 4 position and/or in case that the object compound (I) has freeamino group, it may be transformed into its pharmaceutically acceptablesalt as aforementioned by a conventional method.

The object compound (I) and pharmaceutically acceptable salt thereof ofthe present invention are all novel compounds which exhibit highantibacterial activity, inhibiting the growth of a wide variety ofpathogenic microorganisms including Gram-positive and Gram-negativebacteria and are useful as antibacterial agents. Particularly, it is tobe noted that the object compound (I), i.e., syn-isomer has much higherantibacterial activities than the corresponding anti-isomer to thecompound (I), and accordingly the object compound (I), i.e., syn-isomeris characterized by having much superiority to the correspondinganti-isomer in the therapeutic value.

Now, in order to show the utility of the object compound (I), withregard to some representative compounds of this invention, there areshown the test data on the in vitro anti-bacterial activity, the testdata on in vivo, i.e. the protecting effect against experimentalinfections and the acute toxicity in the following. Additionally, thereare also shown the comparative test data on in vitro antibacterialactivities relating to the corresponding anti-isomer to the objectcompound (I) for the reference's sake in the following.

Test compounds

(1)7-[2-Methoxyimino-2-(3-hydroxyphenyl)acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylicacid (syn isomer)

(2)7-[2-Methoxyimino-2-(3-hydroxyphenyl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer)

(3)7-[2-Methoxyimino-2-(3-hydroxyphenyl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (anti isomer)

(4)7-[2-Methoxyimino-2-(3-hydroxyphenyl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer)

(5)-7-[2-Methoxyimino-2-(3-acetoxyphenyl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer)

(6)7-[2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer)

(7)7-[2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (anti isomer)

(8)7-[2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]cephalosporanicacid (syn isomer)

(9)7-[2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]cephalosporanicacid (anti isomer)

(10)7-[2-Methoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer)

(11)7-[2-Methoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (anti isomer)

(12)7-[2-Methoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acetamido]cephalosporanicacid (syn isomer)

(13)7-[2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylicacid (syn isomer)

(14)7-[2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer)

(15)7-[2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-hydroxymethyl-3-cephem-4-carboxylicacid (syn isomer)

(16)7-[2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer)

(17)7-[2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-(4-methyl-4H-1,2,4-triazol-3-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer)

(18)7-[2-Methoxyimino-2-{2-(2,2,2-trifluoroacetamido)-1,3-thiazol-4-yl}acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylicacid (syn isomer)

1. In Vitro Antibacterial Activity Test Method

In vitro antibacterial activity was determined by the two-foldagar-plate dilution method as described below.

One loopful of an overnight culture of each test strain inTrypticase-soy broth (10⁸ viable cells per ml.) was streaked on heartinfusion agar (HI-agar) containing graded concentrations of antibiotics,and the minimal inhibitory concentration (MIC) was expressed in terms ofμg/ml. after incubation at 37° C. for 20 hours.

    __________________________________________________________________________    Test Results                                                                          MIC (μg/ml)                                                                Test Compounds                                                        Test Bacteria                                                                         (1)                                                                              (2)                                                                              (3) (4)                                                                              (5)                                                                              (6)                                                                              (7)                                                                              (8)                                                                              (9)                                                                              (10)                                                                             (11)                                                                             (12)                                                                             (13)                                                                             (14)                                                                             (15)                                                                             (16)                                                                             (17)                                                                             (18)              __________________________________________________________________________    Escherichia coli                                                                      1.56                                                                             1.56                                                                             50  3.13                                                                             12.5                                                                             0.20                                                                             12.5                                                                             0.10                                                                             3.13                                                                             0.78                                                                             12.5                                                                             1.56                                                                             1.56                                                                             0.10                                                                             0.78                                                                             0.39                                                                             0.20                                                                             3.13              NIHJ JC-2                                                                     Klebsiella                                                                            0.39                                                                             0.39                                                                             6.25                                                                              0.78                                                                             0.78                                                                             0.10                                                                             6.25                                                                             0.10                                                                             1.56                                                                             1.56                                                                             3.13                                                                             1.56                                                                             0.05                                                                             0.20                                                                             0.05                                                                             0.10                                                                             0.20                                                                             0.05              pneumoniae 417                                                                Proteus mirabilis                                                                     0.78                                                                             0.78                                                                             25  0.78                                                                             1.56                                                                             0.10                                                                             3.13                                                                             0.05                                                                             0.78                                                                             0.39                                                                             3.13                                                                             0.78                                                                             0.025                                                                            0.10                                                                             0.10                                                                             0.39                                                                             0.39                                                                             0.025             525                                                                           __________________________________________________________________________

As clearly seen from the above test results, the object compounds (I) ofthe present invention, i.e., syn-isomers have much higher antibacterialactivity as compared with the corresponding anti-isomers thereof.

2. Protecting Effect Against Experimental Infections in Mice Test Method

Male ICR strain mice aged 4 weeks, each weighing 20-23 g were used ingroups of 8 mice. The test bacteria were cultured overnight at 37° C. onHI-agar and then suspended in 2.5-5% mucin solution to obtain thesuspension corresponding to each challenge cells. Mice were inoculatedintraperitoneally with 0.5 ml of the suspension. A solution containingeach test compounds was given subcutaneously to the mice in variousdosage one hour after challenge. The ED₅₀ values were calculated fromthe number of surviving mice for each dosage after one week ofobservation.

    __________________________________________________________________________    Test Results                                                                  Protecting Effect against Experimental Infections in Mice                     __________________________________________________________________________                    MIC of used strain (μg/ml)                                                                        ED.sub.50 (S.C.)(mg/mouse)                       Challenge                                                                           viable                                                                             Test Compounds    Test Compounds                         Test Bacteria                                                                           cells/mouse                                                                         cells/ml                                                                           (8) (14)                                                                              (5)                                                                              (4)                                                                              CET*                                                                              (8) (14)                                                                              (5)                                                                              (4)                                                                              CET                      __________________________________________________________________________    Escherichia coli 29                                                                     6 × 10.sup.6                                                                  10.sup.8                                                                           0.2 ≦0.03                                                                      0.78                                                                             0.78                                                                             12.5                                                                              <0.005                                                                            <0.005                                                                            0.081                                                                            0.111                                                                            1.402                                    10.sup.6                                                                           ≦0.03                                                                      ≦0.03                                                                      0.39                                                                             0.78                                                                             3.13                                       __________________________________________________________________________     *CET: 7(2-Thienyl)acetamidocephalosporanic acid                          

    MIC of used strain (μg/ml)            ED.sub.50  (S.C.)(mg/mouse)                    Challenge      Test Compounds  Test Compounds                       Test Bacteria                                                                           cells/mouse                                                                          viable cells/ml                                                                       (13) (12)                                                                              Cefuroxime*                                                                          (13) (12)                                                                              Cefuroxime                  __________________________________________________________________________    Serratia marcesens 4                                                                    1.0 × 10.sup.6                                                                 10.sup.8                                                                              25   200 400    <0.156                                                                             0.018                                                                             4.329                                        10.sup.6                                                                              ≦0.025                                                                      6.25                                                                              50                                          __________________________________________________________________________     *Cefuroxime:                                                                  7[2Methoxyimino-2-(2-furyl)acetamido3-carbamoyloxymethyl-3-cephem-4-carbo    ylic acid (syn isomer)                                                    

    MIC of used strain (μ g/ml)            ED.sub.50 (S.C.)(mg/mouse)                                        Test Compounds                                                                            Test Compounds                      Test Bacteria                                                                           Challenge cells/mouse                                                                    viable cells/ml                                                                        (6)  Cefuroxime                                                                           (6)   Cefuroxime                    __________________________________________________________________________    Escherichia coli 100                                                                    3.5 × 10.sup.4                                                                     10.sup.8 1.56 12.5   0.023 1.158                                              10.sup.6 0.2  12.5                                       __________________________________________________________________________                         MIC of used strain (μg/ml)                                                                       ED.sub.50 (S.C.)(mg/mouse)                                      Test Compounds                                                                              Test Compounds                     Test Bacteria                                                                           Challenge cells/mouse                                                                    viable cells/ml                                                                       (2) (1) CEZ Na*                                                                             (2) (1) CEZ Na                     __________________________________________________________________________    Escherichia coli 29                                                                     5.5 × 10.sup.5                                                                     10.sup.8                                                                              0.78                                                                              0.39                                                                              3.13  0.386                                                                             0.079                                                                             0.182                                           10.sup.6                                                                              ≦0.1                                                                       0.2 0.78                                     __________________________________________________________________________     *CEZ Na: Sodium                                                               7[2(1H--tetrazol1-yl)acetamido3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethy    -3-cephem-4-carboxylate                                                   

3. Acute Toxicity in Mice

The same strain mice as aforesaid protecting test against experimentalinfections were used in groups of 10 mice. Test compound (8) (2 g) wasadministered intravenously to said mice. All mice survived withoutshowing any disorder after one week observation.

For therapeutic administration, the object compound (I) of the presentinvention is used in the form of conventional pharmaceutical preparationwhich contains said compound, as an active ingredient, in admixture witha pharmaceutically acceptable carriers such as an organic or inorganicsolid or liquid excipient which is suitable for oral, parenteral orexternal administration. The pharmaceutical preparations may be in solidform such as capsule, tablet, dragee, ointment or suppository, or inliquid form such as solution, suspension, or emulsion. If needed, theremay be included in the above preparations auxiliary substances,stabilizing agents, wetting or emulsifying agents, buffers and the othercommonly used additives.

While the dosage of the compounds may vary from and also depend upon theage, conditions of the patient, a kind of disease, a kind of thecompound (I) to be applied, etc., an average single dose of about 50mg., 100 mg., 250 mg., and 500 mg. of the object compound (I) of thepresent invention has proved to be effective in treating diseasesinfected by pathogenic bacteria.

In general, amounts between 1 mg. and about 1000 mg. or even more may beadministered to a patient.

The following examples are given for the purpose of illustrating thepresent invention:

EXAMPLE 1

A mixture of dimethylformamide (2.81 g.) and phosphorus oxychloride(5.36 g.) was warmed at 40° C. for 1 hour. After cooling, methylenechloride (60 ml.) was added thereto and distilled off. To the residuewas added dry ethyl acetate (50 ml.). Then,2-methoxyimino-2-(3-hydroxyphenyl)acetic acid (syn isomer) (6.83 g.) wasadded thereto at 5° C. with stirring under ice-cooling. The resultantmixture was then stirred for 50 minutes at the same temperature. On theother hand,7-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (11.5 g.) and bis(trimethylsilyl)acetamide (28.4 g.) were dissolvedin dry ethyl acetate (150 ml.) and stirred under cooling, to which wasat a time added the above obtained solution at -40° C. After stirringfor 2 hours at -30° to -20° C., a saturated sodium chloride aqueoussolution (100 ml.) was added at -20° C. to the reaction mixture. Themixture was stirred for 5 minutes. The precipitates were filtered offand ethyl acetate layer in the filtrate was separated. The aqueous layerwas extracted twice with ethyl acetate (50 ml.). Ethyl acetate layerseparated from the filtrate and the extracts were combined. The combinedethyl acetate solution was washed with a saturated sodium chlorideaqueous solution (50 ml.). To the ethyl acetate layer was addedactivated charcoal and the mixture was stirred for 5 minutes andfiltered. Water (100 ml.) was added to the filtrate and the resultingmixture was adjusted to pH 7 with an aqueous solution of sodiumbicarbonate. The aqueous layer was separated and washed with methylenechloride. After the aqueous layer was separated, methylene chloride wasremoved from the aqueous layer by bubbling of nitrogen gas underice-cooling. After filtration, the aqueous layer was adjusted to pH 2with 10% hydrochloric acid with stirring and ice-cooling. Precipitatingcrystals were collected by filtration, washed with water and dried togive7-[2-methoxyimino-2-(3-hydroxyphenyl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (11.3 g.).

I.R. spectrum (Nujol) 3250, 1770, 1725, 1670 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.76 (1H, d, J=8 Hz), 6.7-7.40 (4H,m), 5.86 (1H, dd, J=5,8 Hz), 5.18 (1H, d, J=5 Hz), 4.34 (2H, AB_(q),J=13 Hz), 3.92 (6H, s), 3.72 (2H, AB_(q), J=17 Hz).

EXAMPLE 2

A mixture of dimethylformamide (1.41 g.) and phosphorus oxychloride(2.95 g.) was warmed for 1 hour at 40° C. After cooling, methylenechloride (30 ml.) was added thereto and distilled off. To the residuewas added dry ethyl acetate (20 ml.).2-Methoxyimino-2-(3-hydroxyphenyl)acetic acid (syn isomer) (3.4 g.) wasadded thereto with stirring and ice-cooling and the mixture was stirredfor 30 minutes under ice-cooling. On the other hand,7-amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (4.8 g.) wasdissolved in a solution of trimethylsilylacetamide (27.5 g.) in dryethyl acetate (70 ml.). To the solution was at a time added the aboveobtained solution at -30° C. and the mixture was stirred for 1.5 hoursat -30° to -10° C. A saturated sodium chloride aqueous solution wasadded to the reaction mixture at -20° C. The ethyl acetate layer wasseparated and the aqueous layer was extracted with ethyl acetate. Twoethyl acetate layers were combined, washed with a sodium chlorideaqueous solution and treated with activated charcoal. After filtration,water (100 ml.) was added to the filtrate and the mixture was adjustedto pH 7 with a sodium bicarbonate aqueous solution. The aqueous layerwas separated and ethyl acetate was added thereto. The mixture wasadjusted to pH 5 with 10% hydrochloric acid and the aqueous layer wasseparated. Ethyl acetate was added thereto and the mixture was adjustedto pH 2 with 10% hydrochloric acid. The ethyl acetate layer wasseparated and the aqueous layer was further extracted with ethylacetate. Two ethyl acetate layers were combined, washed with a sodiumchloride aqueous solution and dried over magnesium sulfate. The solventwas distilled off and the residue was pulverized with diisopropyl ether.The powder was collected by filtration and dried to give7-[2-methoxyimino-2-(3-hydroxyphenyl)acetamido]-3-carbamoyl-oxymethyl-3-cephem-4-carboxylicacid (syn isomer) (3.26 g.).

I.R. spectrum (Nujol) 3500-3200, 1765, 1720, 1655 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.64 (1H, d, J=8 Hz), 6.70-7.20 (4H,m), 6.78 (2H, s), 5.92 (1H, dd, J=5,8 Hz), 5.16 (1H, d, J=5 Hz), 4.73(2H, AB_(q), J=13 Hz), 3.91 (3H, s), 3.72 (2H, AB_(q), J=17 Hz).

7-[2-Methoxyimino-2-(3-hydroxyphenyl)acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylicacid (syn isomer) (1.98 g.) was suspended in water (15 ml.) anddissolved by adding sodium bicarbonate (0.35 g.) with stirring atambient temperature. The solution was lyophilized and dried to givesodium7-[2-methoxyimino-2-(3-hydroxyphenyl)acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylate(syn isomer) (1.9 g.).

I.R. spectrum (Nujol) 3300, 1765, 1715, 1665 cm⁻¹

N.M.R. spectrum (D₂ O, δ) ppm: 6.83-7.60 (4H, m), 5.85 (1H, d, J=5 Hz),5.17 (1H, d, J=5 Hz), 4.77 (2H, AB_(q), J=13 Hz), 4.03 (3H, s), 3.48(2H, AB_(q), J=18 Hz).

EXAMPLE 3

A mixture of dry dimethylformamide (0.18 g.) and phosphorus oxychloride(0.38 g.) was stirred for 30 minutes at 40° C. Dry methylene chloride(15 ml.) was added thereto and distilled off under reduced pressure. Tothe residue was added dry ethyl acetate (15 ml.) and2-methoxyimino-2-(3-chloro-4-hydroxyphenyl)acetic acid (syn isomer)(0.53 g.) was added thereto with stirring at -20° C. The mixture wasstirred for 1 hour below -10° C. On the other hand, a mixture of7-amino-3-trichloroacetylcarbamoyloxymethyl-3-cephem-4-carboxylic acid(1 g.), trimethylsilylacetamide (5 g.) and dry ethyl acetate (25 ml.)was stirred for 1 hour at ambient temperature. To this solution wasdropwise added the above obtained solution with stirring below -10° andthe resulting mixture was stirred for 2 hours at the same temperature.Water (50 ml.) and ethyl acetate (50 ml.) were added to the reactionmixture at -20° C. and the mixture was shaken. The organic layercontaining7-[2-methoxyimino-2-(3-chloro-4-hydroxyphenyl)acetamido]-3-trichloroacetylcarbamoyloxymethyl-3-cephem-4-carboxylicacid (syn isomer) was adjusted to pH 7.0 by adding water (50 ml.) andsodium bicarbonate and the mixture was stirred for 2 hours at ambienttemperature. Ethyl acetate (50 ml.) was added to the aqueous layer andthe mixture was adjusted to pH 5.0 with 10% hydrochloric acid. Theaqueous layer was separated, adjusted to pH 2.0 with 10% hydrochloricacid and extracted with ethyl acetate (50 ml.). The extract was washedwith ice-water and dried over magnesium sulfate. The solvent wasdistilled off under reduced pressure. The residue was thoroughly washedwith ether, collected by filtration and dried to give7-[2-methoxyimino-2-(3-chloro-4-hydroxyphenyl)acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer) (0.3 g.).

I.R. spectrum (Nujol) 3450, 3300, 1770, 1730, 1715, 1660, 1650, 1600cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.72 (1H, d, J=8 Hz), 7.48 (1H, d,J=2 Hz), 7.40 (1H, dd, J=2,8 Hz), 6.98 (1H, d, J=8 Hz), 6.60 (2H, s),5.70 (1H, q, J=5 Hz), 5.20 (1H, d, J=5 Hz), 4.74 (2H, AB_(q), J=13 Hz),3.90 (3H, s), 3.50 (2H, AB_(q), J=18 Hz).

EXAMPLE 4

2-Methoxyimino-2-(3-hydroxyphenyl)acetic acid (syn isomer) (1.1 g.) and7-amino-3-trichloroacetylcarbamoyloxymethyl-3-cephem-4-carboxylic acid(2.35 g.) were reacted and post-treated according to a similar manner tothat of Example 3 to give7-[2-methoxyimino-2-(3-hydroxyphenyl)acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylicacid (syn isomer) (0.5 g.). This compound is identified with thecompound obtained in Example 2 by I.R. and N.M.R. spectra.

EXAMPLE 5

(a) 2-t-Butoxycarbonylmethoxyimino-2-(3-chloro-4-hydroxyphenyl)aceticacid (syn isomer) (1 g.) and7-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (1 g.) were reacted according to similar manners to those ofExamples 1 and 2 to give powder of7-[2-t-butoxycarbonylmethoxyimino-2-(3-chloro-4-hydroxyphenyl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (1.5 g.).

(b) The powder obtained in Example 5(a) (1.5 g.) was added to a mixtureof anisole (1.5 ml.) and trifluoroacetic acid (6 ml.) and the resultingmixture was stirred for 30 minutes at ambient temperature. The reactionmixture was adjusted to pH 8 by adding a sodium bicarbonate aqueoussolution (50 ml.), ethyl acetate (50 ml.) and sodium bicarbonate underice-cooling. The aqueous layer was separated, adjusted to pH 5.0 with10% hydrochloric acid and washed with ethyl acetate (50 ml.). Theaqueous layer was further adjusted to pH 2.0 with 10% hydrochloric acidand extracted with ethyl acetate (100 ml.). The extract was washed withwater and dried over magnesium sulfate. The solvent was distilled offunder reduced pressure and the residue was dissolved in pH 5.0 acetatebuffer and subjected to column chromatography on Woelm neutral alumina(trade mark: made by ICN Company) using pH 5.0 acetate buffer asdeveloping solvent. The eluate was adjusted to pH 2.0 with 10%hydrochloric acid under ice-cooling. Precipitating materials werecollected by filtration, washed with water and dried to give7-[2-carboxymethoxyimino-2-(3-chloro-4-hydroxyphenyl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (0.5 g.), mp 145° to 148° C. (dec.).

I.R. spectrum (Nujol) 3400, 3200-3300, 2500-2600, 1780, 1720, 1670, 1600cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.70 (1H, d, J=8 Hz), 7.50 (1H, d,J=2 Hz), 7.45 (1H, dd, J=2,8 Hz), 7.10 (1H, d, J=8 Hz), 5.90 (1H, q, J=5Hz), 5.22 (1H, d, J=5 Hz), 4.70 (2H, s), 4.35 (2H, AB_(q), J=13 Hz),3.95 (3H, s), 3.75 (2H, AB_(q), J=18 Hz).

EXAMPLE 6

(a) 2-(1-t-Butoxycarbonylethoxyimino)-2-(3-chloro-4-hydroxyphenyl)aceticacid (syn isomer) (2 g.) and7-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (2 g.) were reacted according to similar manners to those ofExamples 1 and 2 to give powder of7-[2-(1-t-butoxycarbonylethoxyimino)-2-(3-chloro-4-hydroxyphenyl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (3.6 g.).

(b) The powder obtained in Example 6(a) (3.6 g.), anisole (4 ml.) andtrifluoroacetic acid (16 ml.) were reacted according to a similar mannerto that of Example 5(b) to give yellow powder of7-[2-(1-carboxyethoxyimino)-2-(3-chloro-4-hydroxyphenyl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (2.0 g.), mp 147° to 151° C. (dec.).

I.R. spectrum (Nujol) 3500, 3250, 2500-2600, 1780, 1730, 1660, 1630,1600 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.62 (1H, d, J=8 Hz), 7.46 (1H, d,J=2 Hz), 7.34 (1H, dd, J=2,8 Hz), 7.04 (1H, d, J=8 Hz), 5.90 (1H, q, J=5Hz), 5.22 (1H, d, J=5 Hz), 4.73 (1H, q, J=6 Hz), 4.33 (2H, AB_(q), J=13Hz), 4.00 (3H, s), 3.73 (2H, AB_(q), J=18 Hz), 1.37 (3H, d, J=6 Hz).

EXAMPLE 7

The following compounds were obtained according to similar manners tothose of Examples 1 and 2.

(1)7-[2-Methoxyimino-2-(3-hydroxyphenyl)acetamido]-3-(4H-1,2,4-triazol-3-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. spectrum (Nujol) 3250, 1775, 1710, 1665 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.67 (1H, d, J=8 Hz), 8.40 (1H, s),6.70-7.43 (4H, m), 5.82 (1H, dd, J=5,8 Hz), 5.13 (1H, d, J=5 Hz), 4.18(2H, AB_(q), J=13 Hz), 3.90 (3H, s), 3.67 (2H, broad s).

(2)7-[2-Methoxyimino-2-(3-hydroxyphenyl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. spectrum (Nujol) 3250, 1780, 1720, 1670 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.78 (1H, d, J=8 Hz), 9.55 (1H, s),6.70-7.40 (4H, m), 5.89 (1H, dd, J=5,8 Hz), 5.22 (1H, d, J=5 Hz), 4.46(2H, AB_(q), J=13 Hz), 3.92 (3H, s), 3.76 (2H, AB_(q), J=18 Hz).

(3)7-[2-Methoxyimino-2-(3-hydroxyphenyl)acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. spectrum (Nujol) 3250, 1780, 1720, 1670 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.72 (1H, d, J=8 Hz), 6.62-7.40 (4H,m), 5.94 (1H, dd, J=5,8 Hz), 5.18 (1H, d, J=5 Hz), 4.18 (2H, AB_(q),J=13 Hz), 3.89 (3H, s), 3.70 (2H, AB_(q), J=17 Hz), 2.65 (3H, s).

(4) 7-[2-Methoxyimino-2-(3-hydroxyphenyl)acetamido]-cephalosporanic acid(syn isomer).

I.R. spectrum (Nujol) 3250, 1785, 1740, 1720 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.78 (1H, d, J=8 Hz), 6.86-7.36 (4H,m), 5.86 (1H, dd, J=5,8 Hz), 5.18 (1H, d, J=5 Hz), 4.84 (2H, AB_(q),J=13 Hz), 3.98 (3H, s), 3.54 (2H, AB_(q), J=17 Hz), 2.00 (3H, s).

(5)7-[2-Methoxyimino-2-(3-methoxyphenyl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. spectrum (Nujol) 3250, 1780, 1720, 1670 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.78 (1H, d, J=8 Hz), 6.95-7.54 (4H,m), 5.94 (1H, dd, J=5,8 Hz), 5.18 (1H, d, J=5 Hz), 4.12 (2H, AB_(q),J=13 Hz), 3.92 (6H, s), 3.76 (3H, s), 3.72 (2H, AB_(q), J=18 Hz).

(6)7-[2-Methoxyimino-2-(4-hydroxyphenyl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. spectrum (Nujol) 3250, 1780, 1720, 1670 cm¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.70 (1H, d, J=8 Hz), 7.44 (2H, d,J=8 Hz), 6.84 (2H, d, J=8 Hz), 5.86 (1H, dd, J=5,8 Hz), 5.18 (1H, d, J=5Hz), 4.34 (2H, AB_(q), J=13 Hz), 3.93 (3H, s), 3.87 (3H, s), 3.74 (2H,AB_(q), J=18 Hz).

(7)7-[2-Methoxyimino-2-(3-chloro-4-hydroxyphenyl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 145° to 148° C. (dec).

I.R. spectrum (Nujol) 3500, 3250, 2500-2600, 1780, 1720, 1655, 1625,1600 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 10.80 (1H, broad s), 9.68 (1H, d, J=2Hz), 7.46 (1H, d, J=2 Hz), 7.32 (1H, q, J=2,8 Hz), 7.00 (1H, d, J=8 Hz),5.80 (1H, q, J=5 Hz), 5.16 (1H, d, J=5 Hz), 4.28 (2H, AB_(q), J=13 Hz),3.92 (3H, s), 3.87 (3H, s), 3.72 (2H, AB_(q), J=18 Hz).

(8)7-[2-Methoxyimino-2-(3-chloro-4-methoxyphenyl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 143° to 145° C. (dec.).

I.R. spectrum (Nujol) 3300, 2500-2600, 1785, 1730, 1670, 1630, 1600 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.76 (1H, d, J=8 Hz), 7.56 (1H, d,J=2 Hz), 7.48 (1H, dd, J=2,8 Hz), 7.22 (1H, d, J=8 Hz), 5.84 (1H, q, J=5Hz), 5.18 (1H, d, J=5 Hz), 4.27 (2H, AB_(q), J=13 Hz), 3.90 (6H, s),3.88 (3H, s), 3.70 (2H, AB_(q), J=18 Hz).

(9)7-[2-Methoxyimino-2-(3-nitro-4-hydroxyphenyl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 149° to 152° C. (dec.).

I.R. spectrum (Nujol) 3400-3450, 3200, 2500-2600, 1780, 1720, 1660,1620, 1600, 1535, 1350 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.72 (1H, d, J=8 Hz), 7.97 (1H, d,J=2 Hz), 7.72 (1H, dd, J=2,8 Hz), 7.21 (1H, d, J=8 Hz), 5.82 (1H, q, J=5Hz), 5.16 (1H, d, J=5 Hz), 4.3 (2H, AB_(q), J=13 Hz), 3.92 (3H, s), 3.87(3H, s), 3.72 (2H, AB_(q), J=18 Hz).

(10)7-[2-Allyloxyimino-2-(3-chloro-4-hydroxyphenyl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 163° to 165° C. (dec.).

I.R. spectrum (Nujol) 3200-3300, 2500-2600, 1780, 1720, 1670, 1600 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.70 (1H, d, J=8 Hz), 7.40 (1H, d,J=2 Hz), 7.30 (1H, dd, J=2,8 Hz), 6.95 (1H, d, J=8 Hz), 5.80 (2H, m),5.30 (2H, d, J=8 Hz), 5.10 (1H, d, J=5 Hz), 4.60 (2H, d, J=5 Hz), 4.27(2H, AB_(q), J=13 Hz), 3.85 (3H, s), 3.65 (2H, AB_(q), J=18 Hz).

(11)7-[2-Allyloxyimino-2-(3-hydroxyphenyl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 149° to 152° C. (dec.).

I.R. spectrum (Nujol) 3250-3350, 2550-2600, 1780, 1730, 1670, 1650, 1600cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.70 (1H, d, J=8 Hz), 7.2-6.8 (4H,m), 6.1-5.8 (2H, m), 5.35 (2H, d, J=8 Hz), 5.17 (1H, d, J=5 Hz), 4.7(2H, d, J=5 Hz), 4.17 (2H, AB_(q), J=13 Hz), 3.93 (3H, s), 3.75 (2H,AB_(q), J=18 Hz).

(12) Sodium7-[2-methoxyimino-2-(3-hydroxyphenyl)acetamido]-cephalosporanate (synisomer).

I.R. spectrum (Nujol) 3250, 1765, 1730, 1665 cm⁻¹

N.M.R. spectrum (D₂ O, δ) ppm: 6.83-7.13 (4H, m), 5.83 (1H, d, J=5 Hz),5.17 (1H, d, J=5 Hz), 4.82 (2H, AB_(q), J=13 Hz), 4.03 (3H, s), 3.50(2H, AB_(q), J=17 Hz), 2.1 (3H, s).

(13)7-[2-(3-Hydroxy-4-bromobenzyloxyimino)-2-(4-hydroxyphenyl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), powder.

I.R. spectrum (Nujol) 3150, 1780, 1720, 1670 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.60 (1H, d, J=8 Hz), 6.72-7.52 (7H,m), 5.80 (1H, dd, J=4,8 Hz), 5.15 (1H, d, J=4 Hz), 5.00 (2H, s), 4.28(2H, AB_(q), J=13 Hz), 3.90 (3H, s), 3.65 (2H, AB_(q), J=18 Hz).

(14)7-[2-(2-Thienylmethoxyimino)-2-(4-hydroxyphenyl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), powder.

I.R. spectrum (Nujol) 3200-3300, 1780, 1720, 1660 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.77 (1H, d, J=8 Hz), 6.7-7.7 (7H,m), 5.83 (1H, dd, J=5,8 Hz), 5.29 (2H, s), 5.15 (1H, d, J=5 Hz), 4.3(2H, AB_(q), J=13 Hz), 3.92 (3H, s), 3.72 (2H, AB_(q), J=18 Hz).

(15)7-[2-Ethoxyimino-2-(3-chloro-4-hydroxyphenyl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), colorless powder, mp 153° to 156° C. (dec.).

I.R. spectrum (Nujol) 3450, 3250, 2550-2600, 1780, 1725, 1665, 1630,1600 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.71 (1H, d, J=8 Hz), 7.50 (1H, d,J=2 Hz), 7.36 (1H, dd, J=2,8 Hz), 7.03 (1H, d, J=8 Hz), 5.83 (1H, q, J=5Hz), 5.17 (1H, d, J=5 Hz), 4.33 (2H, AB_(q), J=13 Hz), 4.17 (2H, q, J=7Hz), 3.97 (3H, s), 3.73 (2H, AB_(q), J=18 Hz), 1.25 (3H, t, J=7 Hz).

(16)7-[2-Allyloxyimino-2-(3-methoxyphenyl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), powder, mp 135° to 138° C. (dec.).

I.R. spectrum (Nujol) 3300, 2600, 1785, 1730, 1670, 1645, 1600 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.82 (1H, d, J=8 Hz), 7.0-7.45 (4H,m), 5.8-6.2 (2H, m), 5.36 (2H, t, J=10 Hz), 5.21 (1H, d, J=5 Hz), 4.72(2H, d, J=5 Hz), 4.36 (2H, AB_(q), J=13 Hz), 3.95 (3H, s), 3.91 (3H, s),3.87 (2H, AB_(q), J=18 Hz).

(17)7-[2-Ethoxyimino-2-(3-hydroxyphenyl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), yellow powder, mp 145° to 148° C. (dec.).

I.R. spectrum (Nujol) 3450, 3250, 2500-2600, 1775, 1720, 1665, 1620,1600 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.70 (1H, d, J=8 Hz), 6.8-7.4 (4H,m), 5.90 (1H, q, J=5 Hz), 5.20 (1H, d, J=5 Hz), 4.36 (2H, AB_(q), J=13Hz), 4.20 (2H, q, J=7 Hz), 4.00 (3H, s), 3.76 (2H, AB_(q), J=18 Hz),1.33 (3H, t, J=7 Hz).

(18)7-[2-Ethoxyimino-2-(3-methoxyphenyl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), pale yellow powder, mp 140° to 143° C. (dec.).

I.R. spectrum (Nujol) 3300, 2500-2600, 1785, 1730, 1670, 1630, 1600 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.71 (1H, d, J=8 Hz), 6.9-7.5 (4H,m), 5.90 (1H, q, J=5 Hz), 5.17 (1H, d, J=5 Hz), 4.33 (2H, AB_(q), J=13Hz), 4.20 (2H, q, J=7 Hz), 3.95 (3H, s), 3.85 (3H, s), 3.75 (2H, AB_(q),J=18 Hz), 1.30 (3H, t, J=7 Hz).

(19)7-[2-Allyloxyimino-2-(3-chloro-4-methoxyphenyl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), pale yellow powder, mp 153° to 156° C. (dec.).

I.R. spectrum (Nujol) 3250, 2600, 1780, 1720, 1670, 1645, 1630, 1600cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.65 (1H, d, J=8 Hz), 7.27 (1H, d,J=2 Hz), 7.20 (1H, dd, J=2,8 Hz), 7.09 (1H, d, J=8 Hz), 5.85-6.15 (2H,m), 5.15 (2H, t, J=9 Hz), 5.05 (1H, d, J=5 Hz), 4.60 (2H, d, J=5 Hz),4.15 (2H, AB_(q), J=13 Hz), 3.95 (3H, s), 3.90 (3H, s), 3.47 (2H,AB_(q), J=18 Hz).

(20)7-[2-Methoxyimino-2-(3-acetoxyphenyl)acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. spectrum (Nujol) 3450, 3250, 1765, 1710, 1655, 1530 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.77 (1H, d, J=8 Hz), 7.6-7.1 (4H,m), 6.56 (2H, s), 5.83 (1H, dd, J=4,8 Hz), 5.20 (1H, d, J=4 Hz), 4.76(2H, AB_(q), J=13 Hz), 3.94 (3H, s), 3.55 (2H, broad s), 2.28 (3H, s).

(21)7-[2-Phenylthiomethoxyimino-2-(3-hydroxyphenyl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. spectrum (Nujol) 3300, 1760, 1660, 1600, 1580, 1520 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.7 (1H, d, J=8 Hz), 7.7-6.7 (9H, m),5.8-5.4 (3H, broad s), 5.06 (1H, d, J=5 Hz), 4.33 (2H, broad s), 3.9(3H, s), 3.56 (2H, broad s).

(22)7-[2-Methoxyimino-2-(3-mesylaminophenyl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 155° C. (dec.).

I.R. spectrum (Nujol) 3300, 1780, 1730, 1670 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.98 (1H, s), 9.81 (1H, d, J=9 Hz),9.62 (1H, s), 5.90 (1H, dd, J=5, 9 Hz), 5.24 (1H, d, J=5 Hz), 4.49 (2H,ABq, J=14 Hz), 3.98 (3H, s), 3.77 (2H, broad s), 2.96 (3H, s).

(23)7-[2-Methoxyimino-2-(3-carbamoyloxyphenyl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. spectrum (Nujol) 3450, 3300, 3200, 1780, 1725, 1670, 1620, 1590,1520 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.77 (1H, d, J=7 Hz), 7.6-6.8 (6H,m), 5.83 (1H, dd, J=4, 7 Hz), 5.17 (1H, d, J=4 Hz), 4.31 (2H, ABq, J=14Hz), 3.96 (6H, s), 3.72 (2H, broad s).

(24)7-[2-Methoxyimino-2-(3-carbamoyloxyphenyl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. spectrum (Nujol) 3250, 1780, 1735, 1675 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.81 (1H, d, J=8 Hz), 9.62 (1H, s),6.7-7.58 (4H, m), 5.87 (1H, dd, J=5, 8 Hz), 5.2 (1H, d, J=5 Hz), 4.25,4.63 (2H, ABq, J=14 Hz), 3.9 (3H, s), 3.7 (2H, broad s).

(25)7-[2-Methoxyimino-2-(3-acetoxyphenyl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. spectrum (Nujol) 3250, 1780, 1740, 1720, 1680 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.86 (1H, d, J=8 Hz), 9.61 (1H, s),7.00-7.65 (4H, m), 5.84 (1H, dd, J=5, 8 Hz), 5.2 (1H, d, J=5 Hz), 4.25,4.63 (2H, ABq, J=14 Hz), 3.92 (3H, s), 3.53, 3.86 (2H, ABq, J=19 Hz),2.3 (3H, s).

(26)7-[2-(3-Phenylallyloxyimino)-2-(3-hydroxyphenyl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 138° to 142° C. (dec.).

I.R. spectrum (Nujol) 3300-3400, 2600, 1780, 1720, 1665, 1600 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.80 (1H, d, J=8 Hz), 6.4-7.4 (11H,m), 5.85 (1H, dd, J=5, 8 Hz), 5.20 (1H, d, J=5 Hz), 4.83 (2H, d, J=5Hz), 4.32 (2H, ABq, J=15 Hz), 3.95 (3H, s), 3.68 (2H, ABq, J=18 Hz).

(27)7-[2-Methoxyimino-2-(4-dimethylaminophenyl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 88° C. (dec.).

I.R. spectrum (Nujol) 3250, 1780, 1730, 1680, 1610 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.63 (1H, d, J=8 Hz), 7.40 (2H, d,J=8 Hz), 6.73 (2H, d, J=8 Hz), 5.83 (1H, dd, J=5, 8 Hz), 5.17 (1H, d,J=5 Hz), 4.33 (2H, ABq, J=13 Hz), 3.97 (3H, s), 3.87 (3H, s), 3.73 (2H,broad s), 3.00 (6H, s).

(28)7-[2-Methoxyimino-2-(3-hydroxyphenyl)acetamido]-3-[1-(2-dimethylaminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. spectrum (Nujol) 1765 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.67 (1H, d, J=9 Hz), 6.72-7.36 (4H,m), 5.78 (1H, dd, J=5, 9 Hz), 5.12 (1H, d, J=5 Hz), 4.55 (2H, broad s),4.30 (2H, broad s), 3.90 (3H, s), 3.40-3.80 (2H, m), 3.14 (2H, broad s),2.48 (6H, s).

(29)7-[2-{2-(2-Hydroxyphenoxy)ethoxyimino}-2-(3-hydroxyphenyl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. spectrum (Nujol) 3270, 1780, 1725, 1670, 1560 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 6.5-7.4 (8H, m), 5.86 (1H, dd, J=5, 8Hz), 5.14 (1H, d, J=5 Hz), 4.0-4.6 (6H, m), 3.92 (3H, s), 3.52, 3.70(2H, AB_(q), J=7 Hz).

EXAMPLE 8

A mixture of dimethylformamide (0.73 g) and phosphorus oxychloride (1.6g) was warmed for 30 minutes at 40° C. Benzene was added thereto and themixture was concentrated. The residue was suspended in ethyl acetate (20ml) and 2-methoxyimino-2-(3-hydroxyphenyl) acetic acid (syn isomer)(1.95 g) was added thereto at -15° to -5° C., after which the resultingmixture was stirred for 30 minutes at the same temperature. On the otherhand, a solution of sodium hydroxide (0.9 g) in water (5 ml) wasdropwise added at 0° to 5° C. over 25 minutes to a suspension of7-aminocephalosporanic acid (2.7 g) in water (12.5 ml) and the mixturewas stirred for 5 minutes, after which acetone (20 ml) was addedthereto. To the resulting mixture containing sodium7-amino-3-hydroxymethyl-3-cephem-4-carboxylate was dropwise added at 0°to 5° C. over 3 minutes the above obtained ethyl acetate solutionkeeping the pH value at 7.5 to 8.5 by adding triethylamine. Afterstirring for 30 minutes, the organic solvents were distilled off. Theaqueous layer was washed with ethyl acetate (20 ml), adjusted to pH 2.0with hydrochloric acid and extracted with ethyl acetate (60 ml) at 0° to3° C. The aqueous layer was further extracted with ethyl acetate (30ml). The combined ethyl acetate extracts were washed with a saturatedaqueous solution of sodium chloride and dried. The solvent was distilledoff and the residue was pulverized with diisopropyl ether to give amixture of7-[2-methoxyimino-2-(3-hydroxyphenyl)acetamido]-3-hydroxymethyl-3-cephem-4-carboxylicacid (syn isomer) (I) and6-[2-methoxyimino-2-(3-hydroxyphenyl)acetamido]-5a,6-dihydro-3H,7H-azeto[2,1-b]-furo[3,4-d][1,3]thiazine-1,7(4H)-dione(synisomer) (II) (2.64 g).

I.R. spectrum of (I) (Nujol) 3250, 1785, 1755, 1660, 1600, 1570, 1540cm⁻¹

N.M.R. spectrum of (I) (d₆ -DMSO, δ) ppm: 9.83 (1H, d, J=8 Hz), 7.5-6.75(4H, m), 5.8 (1H, dd, J=5,8 Hz), 5.21 (1H, d, J=5 Hz), 4.3 (2H, broads), 3.95 (3H, s), 3.63 (2H, broad s).

I.R. spectrum of (II) (Nujol) 3250, 1785, 1755, 1660, 1600, 1570, 1540cm⁻¹

N.M.R. spectrum of (II) (d₆ -DMSO, δ) ppm: 9.83 (1H, d, J=8 Hz),7.5-6.75 (4H, m), 6.02 (1H, dd, J=5, 8 Hz), 5.21 (1H, d, J=5 Hz), 5.07(2H, broad s), 3.95 (3H, s), 3.84 (2H, broad s).

EXAMPLE 9

7-[2-Methoxyimino-2-(3-hydroxyphenyl)acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylicacid (syn isomer) (0.23 g) was dissolved in pyridine (1 ml) withstirring and ice-cooling, and acetyl chloride (0.082 g) was addedthereto. The mixture was stirred for 40 minutes under ice-cooling. Thereaction mixture was poured into ice-water, acidified with hydrochloricacid and extracted with ethyl acetate. The extract was washed with asaturated aqueous solution of sodium chloride and dried over magnesiumsulfate. After treating with activated charcoal, it was filtered and thefiltrate was concentrated. The residue was pulverized with diisopropylether to give a mixture of7-[2-methoxyimino-2-(3-acetoxyphenyl)acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylicacid (syn isomer) and7-[2-methoxyimino-2-(3-acetoxyphenyl)acetamido]-3-carbamoyloxymethyl-2-cephem-4-carboxylicacid (syn isomer) (0.18 g).

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.82 (1H, d, J=8 Hz), 9.77 (1H, d,J=8 Hz), 7.6-7.1 (8H, m), 6.60 (1H, s), 6.56 (2H, s), 5.83 (1H, dd, J=4,8 Hz), 5.60 (1H, dd, J=4,8 Hz), 5.24 (1H, d, J=4 Hz), 5.20 (1H, d, J=4Hz), 4.84 (1H, s), 4.76 (2H, ABq, J=13 Hz), 4.56 (2H, broad s), 3.94(6H, s), 3.55 (2H, broad s), 2.28 (6H, s).

EXAMPLE 10

The following compounds were obtained according to a similar manner tothat of Example 9.

(1)7-[2-Methoxyimino-2-(3-acetoxyphenyl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. spectrum (Nujol) 3250, 1780, 1740, 1720, 1680 cm⁻¹

N.M.R. spectrum (d6-DMSO, δ) ppm: 9.86 (1H, d, J=8 Hz), 9.61 (1H, s),7.00-7.65 (4H, m), 5.84 (1H, dd, J=5, 8 Hz), 5.2 (1H, d, J=5 Hz), 4.25,4.63 (2H, ABq, J=14 Hz), 3.92 (3H, s), 3.53, 3.86 (2H, ABq, J=19 Hz),2.3 (3H, s).

(2)7-[2-Methoxyimino-2-(3-carbamoyloxyphenyl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. spectrum (Nujol) 3450, 3300, 3200, 1780, 1725, 1670, 1620, 1590,1520 cm⁻¹

N.M.R. spectrum (d6-DMSO, δ) ppm: 9.77 (1H, d, J=7 Hz), 7.6-6.8 (6H, m),5.83 (1H, dd, J=4, 7 Hz), 5.17 (1H, d, J=4 Hz), 4.31 (2H, ABq, J=14 Hz),3.96 (6H, s), 3.72 (2H, broad s).

(3)7-[2-Methoxyimino-2-(3-carbamoyl-oxyphenyl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. spectrum (Nujol) 3250, 1780, 1735, 1675 cm⁻¹

N.M.R. spectrum (d6-DMSO, δ) ppm: 9.81 (1H, d, J=8 Hz), 9.62 (1H, s),6.7-7.58 (4H, m), 5.87 (1H, dd, J=5, 8 Hz), 5.2 (1H, d, J=5 Hz), 4.25,4.63 (2H, ABq, J=14 Hz), 3.9 (3H, s), 3.7 (2H, broad s).

EXAMPLE 11

Phosphorus oxychloride (0.26 g.) was added under ice-cooling todimethylformamide (0.15 g.) and the mixture was warmed at 40° C. for 1hour. Ethyl acetate (1.5 ml.) was added thereto and to the mixture wasat a time added 2-methoxyimino-2-(2-methyl-1,3-thiazol-4-yl)acetic acid(syn isomer) (0.3 g.) with stirring and ice-cooling, after which theresulting mixture was stirred for 20 minutes at 0° to 5° C. On the otherhand, bis(trimethylsilyl)acetamide (1.2 g.) was added to a suspension of7-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (0.53 g.) in ethyl acetate (7 ml.) and the mixture was stirred atambient temperature. To this solution was dropwise added the aboveobtained ethyl acetate solution at -20° C. and the mixture was stirredfor 2 hours at -10° to -20° C. Water (20 ml.) was added to the reactionmixture below -25° C. and ethyl acetate (20 ml.) was added thereto,after which the mixture was stirred. An insoluble material was filteredoff and the ethyl acetate layer was separated. Water (15 ml.) was addedto the ethyl acetate layer and the mixture was adjusted to pH 7.5 with asaturated aqueous solution of sodium bicarbonate. The aqueous layer wasseparated, washed with methylene chloride and methylene chloride in theaqueous layer was removed by bubbling of nitrogen gas. The aqueoussolution was adjusted to pH 2.2 with 10% hydrochloric acid andprecipitates were collected by filtration and dried to give7-[2-methoxyimino-2-(2-methyl-1,3-thiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (0.28 g.).

I.R. spectrum (Nujol) 1780, 1710, 1675 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.65 (1H, d, J=10 Hz), 7.66 (1H, s),5.81 (1H, dd, J=5,10 Hz), 5.15 (1H, d, J=5 Hz), 4.31 (2H, AB_(q), J=13Hz), 3.93 (3H, s), 3.90 (3H, s), 3.70 (2H, AB_(q), J=16 Hz), 2.65 (3H,s).

EXAMPLE 12

Phosphorus oxychloride (0.89 g.) and dry dimethylformamide (0.44 g.)were mixed under ice-cooling and then warmed for 30 minutes at 40° C.Dry methylene chloride (20 ml.) was added thereto and then distilledoff. To the residue were added dry ethyl acetate (10 ml.) and then2-methoxyimino-2-[2-(2,2,2-trifluoroacetamido)-1,3-thiazol-4-yl]aceticacid (syn isomer) (1.8 g.) with stirring and ice-cooling. The mixturewas stirred for 40 minutes at the same temperature to give clearsolution. On the other hand, trimethylsilylacetamide (6.36 g.) was addedto a suspension of 7-aminocephalosporanic acid (1.65 g.) in dry ethylacetate (25 ml.) with stirring at ambient temperature, after which themixture was stirred for 1 hour to give a clear solution. To thissolution was at a time added the above-obtained ethyl acetate solutionwith stirring at -20° to -25° C., and the resulting mixture was stirredfor 2 hours at the same temperature. Water (30 ml.) was added to thereaction mixture at the same temperature, and then the mixture wasstirred for 5 minutes at ambient temperature. The ethyl acetate layerwas separated, and the aqueous layer was further extracted with ethylacetate. The ethyl acetate layers were combined and water (50 ml.) wasadded thereto. The mixture was adjusted to pH 7.5 with sodiumbicarbonate, and the aqueous layer was separated. Ethyl acetate (40 ml.)was added to the aqueous layer, and the mixture was adjusted to pH 2.5with 10% hydrochloric acid with stirring and ice-cooling. The ethylacetate layer was separated, and the aqueous layer was further extractedtwice with ethyl acetate (30 ml.). The ethyl acetate layers werecombined, washed with an aqueous solution of sodium chloride and treatedwith activated charcoal. The solvent was distilled off to give7-[2-methoxyimino-2-{2-(2,2,2-trifluoroacetamido)-1,3-thiazol-4-yl}acetamido]cephalosporanicacid (syn isomer) (3.05 g.), mp 205° C. (dec.).

I.R. spectrum (Nujol) 3250, 1790, 1735, 1680, 1650 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.8 (1H, d, J=8 Hz), 7.55 (1H, s),5.88 (1H, dd, J=5,8 Hz), 5.25 (1H, d, J=5 Hz), 4.8 (2H, AB_(q), J=13Hz), 3.95 (3H, s), 3.59 (2H, broad s), 2.03 (3H, s).

EXAMPLE 13

Phosphorus oxychloride (2.0 g.) was at a time added at 5° to 10° C. to asuspension of 2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetic acid(syn isomer) (2 g.) in dry ethyl acetate (20 ml.). After stirring for 20minutes at 7° to 10° C., bis(trimethylsilyl)acetamide (0.4 g.) was addedthereto at the same temperature. After stirring for 10 minutes at 7° to10° C., phosphorus oxychloride (2.0 g.) was dropwise added thereto atthe same temperature. The resulting mixture was stirred for 10 minutesat 7° to 10° C., and dry dimethylformamide (0.8 g.) was dropwise addedthereto at the same temperature. The mixture was stirred for 30 minutesat 7° to 10° C. to give a clear solution. On the other hand,trimethylsilylacetamide (7.35 g.) was added to a suspension of7-aminocephalosporanic acid (2.45 g.) in dry ethyl acetate (8 ml.),after which the mixture was stirred at 40° C. to give a clear solution.To this solution was at a time added the above-obtained ethyl acetatesolution at -15° C., and the resulting mixture was stirred for 1 hour at-10° to -15° C. The reaction mixture was cooled to -30° C., and water(80 ml.) was added thereto. The aqueous layer was separated, adjusted topH 4.5 with sodium bicarbonate and subjected to column chromatography onDiaion HP-20 resin (Trademark: prepared by Mitsubishi ChemicalIndustries Ltd.) using 25% aqueous solution of isopropyl alcohol as aneluent. The eluate was lyophilized to give7-[2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]cephalosporanicacid (syn isomer) (1.8 g.), mp 227° C. (dec.).

I.R. spectrum (Nujol) 3300-3350, 1780, 1740, 1670 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.6 (1H, d, J=8 Hz), 6.8 (1H, s), 5.8(1H, dd, J=5,8 Hz), 5.2 (1H, d, J=5 Hz), 4.87 (2H, AB_(q), J=13 Hz),3.89 (3H, s), 3.6 (2H, broad s), 2.08 (3H, s).

EXAMPLE 14

Phosphorus oxychloride (3.8 g.) was dropwise added at 5° to 8° C. to asuspension of 2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetic acid(syn isomer) (4.0 g.) in dry ethyl acetate (40 ml.). After stirring for30 minutes around 5° C., bis(trimethylsilyl)acetamide (0.86 g.) wasadded thereto at the same temperature. After stirring for 10 minutes atthe same temperature, phosphorus oxychloride (3.8 g.) was dropwise addedthereto at 5° to 8° C., after which the mixture was stirred for 30minutes at the same temperature. Dry dimethylformamide (1.6 g.) wasdropwise added thereto at 5° to 7° C., after which the resulting mixturewas stirred for 30 minutes at the same temperature to give a clearsolution. On the other hand, sodium acetate (3.3 g.) was added to asolution of 7-aminocephalosporanic acid (2.7 g.) in an aqueous solution(20 ml.) of sodium bicarbonate (1.7 g.), and then acetone (20 ml.) wasadded thereto. To this solution was dropwise added the above-obtainedethyl acetate solution with stirring at 0° to 5° C. keeping the pH ofthis solution at 7.0 to 7.5 by 20% aqueous solution of sodium carbonate.The mixture was stirred for 1 hour at the same temperature. An insolublematerial was filtered off, and the aqueous layer in the filtrate wasseparated. The aqueous layer was concentrated under reduced pressure toremove the organic solvents, adjusted to pH 4.5 with sodium bicarbonateand subjected to column chromatography on Diaion HP-20 resin (Trademark:prepared by Mitsubishi Chemical Industries Ltd.) using 25% aqueoussolution of isopropyl alcohol as an eluent. The eluate was lyophilizedto give7-[2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]cephalosporanicacid (syn isomer) (2.8 g.). This compound was identified with thecompound obtained in Example 13 by I.R. and N.M.R. spectra.

EXAMPLE 15

The following compounds were obtained according to similar manners tothose of Examples 11 to 14.

(1)7-[2-Methoxyimino-2-(2-mesylimino-3-methyl-2,3-dihydro-1,3-thiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. spectrum (Nujol) 3250, 1780, 1718, 1675 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.80 (1H, d, J=8 Hz), 7.08 (1H, s),5.80 (1H, dd, J=5,8 Hz), 5.18 (1H, d, J=5 Hz), 4.34 (2H, AB_(q), J=13Hz), 3.99 (3H, s), 3.96 (3H, s), 3.72 (2H, AB_(q), J=17 Hz), 3.66 (3H,s), 2.98 (3H, s).

(2)7-[2-Methoxyimino-2-(2-mesylamino-1,3-thiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. spectrum (Nujol) 3300-3150, 1780, 1710, 1670 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.84 (1H, d, J=8 Hz), 6.97 (1H, s),5.76 (1H, dd, J=5,8 Hz), 5.12 (1H, d, J=5 Hz), 4.33 (2H, AB_(q), J=13Hz), 3.93 (6H, s), 3.74 (2H, AB_(q), J=17 Hz), 2.96 (3H, s).

(3)7-[2-Methoxyimino-2-(2-oxo-2,3-dihydro-1,3-thiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. spectrum (Nujol) 1780, 1665 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 11.67 (1H, s), 9.83 (1H, d, J=8 Hz),6.61 (1H, s), 5.80 (1H, dd, J=5.5,8 Hz), 5.17 (1H, d, J=5.5 Hz), 4.37(2H, broad s), 4.00 (3H, s), 3.96 (3H, s), 3.75 (2H, broad s).

(4)7-[2-Methoxyimino-2-{2-(2,2,2-trifluoroacetamido)-1,3-thiazol-4-yl}acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. spectrum (Nujol) 1790, 1730, 1660 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.73 (1H, d, J=8 Hz), 7.53 (1H, s),5.83 (1H, dd, J=5,8 Hz), 5.15 (1H, d, J=5 Hz), 4.33 (2H, broad s), 3.93(6H, s), 3.72 (2H, broad s).

(5)7-[2-Methoxyimino-2-(2-t-pentyloxycarbonylamino-1,3-thiazol-4-yl)acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. spectrum (Nujol) 3200, 1780, 1720, 1680 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.65 (1H, d, J=8 Hz), 7.28 (1H, s),5.80 (1H, dd, J=5,8 Hz), 5.16 (1H, d, J=5 Hz), 4.38 (2H, AB_(q), J=13Hz), 3.86 (3H, s), 3.70 (2H, AB_(q), J=17 Hz), 2.66 (3H, s), 1.78 (2H,q, J=8 Hz), 1.44 (6H, s), 0.88 (3H, t, J=8 Hz).

(6)7-[2-Allyloxyimino-2-(2-mesylamino-1,3-thiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. spectrum (Nujol) 3100-3300, 1780, 1720, 1675 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.90 (1H, d, J=8 Hz), 7.00 (1H, s),6.07-5.63 (2H, m), 5.43 (2H, d, J=8 Hz), 5.18 (1H, d, J=5 Hz), 4.70 (2H,d, J=5 Hz), 4.37 (2H, broad s), 3.98 (3H, s), 3.75 (2H, broad s), 3.00(3H, s).

(7)7-[2-Allyloxyimino-2-(2-t-pentyloxycarbonylamino-1,3-thiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. spectrum (Nujol) 3250, 1780, 1720, 1678, 1625 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.74 (1H, d, J=8 Hz), 7.31 (1H, s),6.28-5.76 (2H, m), 5.28 (2H, dd, J=8, 16 Hz), 5.18 (1H, d, J=5 Hz), 4.66(2H, d, J=5 Hz), 4.36 (2H, ABq, J=13 Hz), 3.96 (3H, s), 3.74 (2H, ABq,J=17 Hz), 1.80 (2H, q, J=8 Hz), 1.45 (6H, s), 0.89 (3H, t, J=8 Hz).

(8)7-[2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. spectrum (Nujol) 3200, 1765, 1600 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.51 (1H, d, J=8.5 Hz), 7.22 (2H,broad s), 6.72 (1H, s), 5.59 (1H, dd, J=5, 8.5 Hz), 5.00 (1H, d, J=5Hz), 4.35 (2H, ABq, J=12 Hz), 3.90 (3H, s), 3.81 (3H, s), 3.55 (2H, ABq,J=18 Hz).

(9)7-[2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. spectrum (Nujol) 3400-3150, 1770, 1670, 1625 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.66 (1H, d, J=8 Hz), 7.34 (2H, broads), 6.76 (1H, s), 5.78 (2H, dd, J=5,8 Hz), 5.16 (1H, d, J=5 Hz), 4.40(2H, ABq, J=14 Hz), 3.85 (3H, s), 3.70 (2H, ABq, J=17 Hz), 2.68 (3H, s).

(10)7-[2-Allyloxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. spectrum (Nujol) 3100-3400, 1775, 1660, 1625 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.70 (1H, d, J=8 Hz), 6.80 (1H, s),6.30-5.60 (2H, m), 5.24 (2H, dd, J=8,16 Hz), 5.15 (1H, d, J=5 Hz), 4.63(2H, d, J=5 Hz), 4.32 (2H, ABq, J=12 Hz), 3.94 (3H, s), 3.70 (2H, ABq,J=17 Hz).

(11)7-[2-Methoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 145° to 147° C. (dec.).

I.R. spectrum (Nujol) 3150-3400, 1780, 1725, 1680, 1640 cm⁻¹

N.M.R. spectrum (d6-DMSO, δ) ppm: 12.58 (1H, broad s), 9.70 (1H, d, J=8Hz), 9.58 (1H, s), 8.50 (1H, s), 7.40 (1H, s), 5.82 (1H, dd, J=5,8 Hz),5.17 (1H, d, J=5 Hz), 4.43 (2H, ABq, J=13 Hz), 3.88 (3H, s), 3.70 (2H,broad s).

(12)7-[2-Methoxyimino-2-(2-acetamido-1,3-thiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 171° to 173° C. (dec.).

I.R. spectrum (Nujol) 3500, 3250, 1780, 1720, 1670 cm⁻¹

N.M.R. spectrum (d6-DMSO, δ) ppm: 9.65 (1H, d, J=8 Hz), 7.3 (1H, s), 5.8(1H, dd, J=5, 8 Hz), 5.15 (1H, d, J=5 Hz), 4.35 (2H, broad s), 3.97 (3H,s), 3.9 (3H, s), 3.75 (2H, broad s), 2.15 (3H, s).

(13)7-[2-Methoxyimino-2-{2-(2,2,2-trifluoroacetamido)-1,3-thiazol-4-yl}acetamido]-cephalosporanicacid (syn isomer), mp 205° C. (dec.).

I.R. spectrum (Nujol) 3250, 1790, 1735, 1680, 1650 cm⁻¹

N.M.R. spectrum (d6-DMSO, δ) ppm: 9.8 (1H, d, J=8 Hz), 7.55 (1H, s),5.88 (1H, dd, J=5, 8 Hz), 5.25 (1H, d, J=5 Hz), 4.8 (2H, ABq, J=13 Hz),3.95 (3H, s), 3.59 (2H, broad s), 2.03 (3H, s).

(14)7-[2-Methoxyimino-2-{2-(2,2,2-trifluoroacetamido)-1,3-thiazol-4-yl}acetamido]-3-carbamoyloxymethyl-3-cephem-4carboxylicacid (syn isomer).

I.R. spectrum (Nujol) 3500, 3200, 1785, 1700, 1660 cm⁻¹

N.M.R. spectrum (d6-DMSO, δ) ppm: 9.75 (1H, d, J=8 Hz), 8.4 (2H, m),7.53 (1H, s), 6.6 (1H, m), 6.20 (1H, d, J=5 Hz), 5.83 (1H, m), 4.77 (2H,ABq, J=14 Hz), 3.91 (3H, s), 3.55 (2H, m).

(15)7-[2-Methoxyimino-2-{2-(2,2,2-trifluoroacetamido)-1,3-thiazol-4-yl}acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. spectrum (Nujol) 3200, 1780, 1720, 1650 cm⁻¹

N.M.R. spectrum (d6-DMSO, δ) ppm: 9.81 (1H, d, J=8 Hz), 9.6 (1H, m),9.57 (1H, s), 7.56 (1H, s), 5.83 (1H, dd, J=5, 8 Hz), 5.20 (1H, d, J=5Hz), 4.47 (2H, ABq, J=14 Hz), 3.96 (3H, s), 3.72 (2H, ABq, J=18 Hz).

(16)7-[2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-hydroxymethyl-3-cephem-4-carboxylicacid (syn isomer), mp 260° to 270° C. (dec.).

I.R. spectrum (Nujol) 3370, 3270, 1765, 1660, 1610, 1590, 1550 cm⁻¹

N.M.R. spectrum (d6-DMSO, δ) ppm: 9.58 (1H, d, J=8 Hz), 6.76 (1H, s),5.75 (1H, dd, J=5, 8 Hz), 5.12 (1H, d, J=5 Hz), 4.27 (2H, broad s), 3.85(3H, s), 3.57 (2H, broad s).

(17)7-[2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-cephalosporanicacid (syn isomer), mp 227° C. (dec.).

I.R. spectrum (Nujol) 3300-3350, 1780, 1740, 1670 cm⁻¹

N.M.R. spectrum (d6-DMSO, δ) ppm: 9.6 (1H, d, J=8 Hz), 6.8 (1H, s), 5.8(1H, dd, J=5, 8 Hz), 5.2 (1H, d, J=5 Hz), 4.87 (2H, ABq, J=13 Hz), 3.89(3H, s), 3.6 (2H, broad s), 2.08 (3H, s).

(18)7-[2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-carbamoyloxymethyl-3-cepham-4-carboxylicacid (syn isomer), mp 210° to 220° C. (dec.).

I.R. spectrum (Nujol) 3250, 1765, 1650 cm⁻¹

N.M.R. spectrum (d6-DMSO, δ) ppm: 9.64 (1H, d, J=8 Hz), 7.4 (2H, m),6.79 (1H, s), 6.60 (2H, m), 5.77 (1H, dd, J=5, 8 Hz), 5.16 (1H, d, J=5Hz), 4.75 (2H, ABq, J=12 Hz), 3.87 (3H, s), 3.53 (2H, ABq, J=18 Hz).

(19)7-[2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 172° to 175° C. (dec.).

I.R. spectrum (Nujol) 3300, 1770, 1665 cm⁻¹

N.M.R. spectrum (d6-DMSO, δ) ppm: 9.80 (1H, d, J=8 Hz), 9.63 (1H, s),6.95 (1H, s), 6.8 (2H, m), 5.82 (1H, dd, J=5, 8 Hz), 5.22 (1H, d, J=5Hz), 4.48 (2H, ABq, J=15 Hz), 3.97 (3H, s), 3.76 (2H, ABq, J=18 Hz).

(20)7-[2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-(4-methyl-4H-1,2,4-triazol-3-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 185° C. (dec.).

I.R. spectrum (Nujol) 3150-3350, 1770, 1710, 1660, 1630 cm⁻¹

N.M.R. spectrum (d6-DMSO, δ) ppm: 9.61 (1H, d, J=8 Hz), 8.69 (1H, s),6.73 (1H, s), 5.72 (1H, dd, J=4, 8 Hz), 5.1 (1H, d, J=4 Hz), 4.1 (2H,ABq, J=13 Hz), 3.87 (3H, s), 3.65 (2H, broad s), 3.59 (3H, s).

(21)7-[2-Methoxyimino-2-{2-(2,2,2-trifluoroacetamido)-1,3-thiazol-4-yl}acetamido]-3-hydroxymethyl-3-cephem-4-carboxylicacid (syn isomer), mp 155° to 160° C. (dec.).

I.R. spectrum (Nujol) 3250, 1780, 1730, 1660, 1585, 1520 cm⁻¹

N.M.R. spectrum (d6-DMSO, δ) ppm: 9.76 (1H, d, J=8 Hz), 7.57 (1H, s),5.80 (1H, dd, J=4, 8 Hz), 5.15 (1H, d, J=4 Hz), 4.29 (2H, s), 3.93 (3H,s), 3.60 (2H, s).

(22)6-[2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-5a,6-dihydro-3H,7H-azeto[2,1-b]furo[3,4-d][1,3]thiazine-1,7(4H)-dione(syn isomer), mp 210° to 215° C. (dec.).

I.R. spectrum (Nujol) 3270, 1780, 1740, 1655, 1610, 1525 cm⁻¹

N.M.R. spectrum (d6-DMSO, δ) ppm: 9.70 (1H, d, J=8 Hz), 7.26 (2H, broads), 6.77 (1H, s), 5.93 (1H, dd, J=5, 8 Hz), 5.16 (1H, d, J=5 Hz), 5.05(2H, broad s), 3.85 (3H, s), 3.81 (2H, broad s).

(23)7-[2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-[1-(2-dimethylaminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. spectrum (Nujol) 1765 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.56 (1H, d, J=8 Hz), 6.75 (1H, s),5.75 (1H, m), 5.10 (1H, d, J=4 Hz), 4.58 (2H, broad s), 4.32 (2H, broads), 3.82 (3H, s), 3.68 (2H, broad s), 3.20 (2H, broad s), 2.50 (6H, s).

(24)7-[2-Methoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acetamido]cephalosporanicacid (syn isomer).

I.R. spectrum (Nujol) 3280, 1785, 1740, 1700, 1650 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 12.68 (1H, broad s), 9.68 (1H, d, J=8Hz), 8.54 (1H, s), 7.45 (1H, s), 5.86 (1H, dd, J=5,8 Hz), 5.20 (1H, d,J=5 Hz), 4.90 (2H, AB_(q), J=8 Hz), 3.61 (3H, broad s), 2.06 (3H, s).

(25)7-[2-Methoxyimino-2-(2-ethoxycarbonylamino-1,3-thiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. specetum (Nujol) 3200, 1775, 1720, 1680, 1660 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 11.9 (1H, m), 9.70 (1H, d, J=10 Hz),9.55 (1H, s), 7.31 (1H, s), 5.80 (1H, dd, J=5,10 Hz), 5.18 (1H, d, J=5Hz), 4.44 (2H, AB_(q), J=16 Hz), 4.22 (2H, q, J=7 Hz), 3.89 (3H, s),3.72 (2H, AB_(q), J=16 Hz), 1.23 (3H, t, J=7 Hz).

(26)7-[2-Methoxyimino-2-{2-(2,2,2-trifluoroacetamido)-1,3-thiazol-4-yl}acetamido]-3-formyl-3-cephem-4-carboxylicacid (syn isomer) [or this compound can be represented as3-hydroxy-6-[2-methoxyimino-2-{2-(2,2,2-trifluoroacetamido)-1,3-thiazol-4-yl}acetamido]-5a,6-dihydro-3H,7H-azeto[2,1-b]furo[3,4-d][1,3]thiazine-1,7(4H)dione(syn isomer)].

I.R. spectrum (Nujol) 3150, 1790, 1720, 1655, 1560, 1500 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.88 (1H, d, J=8 Hz), 7.60 (1H, s),6.30 (1H, d, J=6 Hz), 6.05 (1H, dd, J=5,8 Hz), 5.23 (1H, d, J=5 Hz),3.96 (3H, s), 3.80 (2H, broad s).

(27)7-[2-Methoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. spectrum (Nujol) 3200-3300, 2600, 1780, 1720, 1690, 1675 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 12.60 (1H, broad s), 9.70 (1H, d, J=8Hz), 8.50 (1H, s), 7.44 (1H, s), 5.88 (1H, dd, J=5,8 Hz), 5.19 (1H, d,J=5 Hz), 4.25 (2H, AB_(q), J=13 Hz), 3.95 (3H, s), 3.85 (3H, s), 3.65(2H, AB_(q), J=18 Hz).

(28)7-[2-Methoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. spectrum (Nujol) 3300, 1780, 1705, 1680 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 12.50 (1H, broad s), 9.67 (1H, d, J=8Hz), 8.50 (1H, s), 7.43 (1H, s), 6.58 (2H, broad s), 5.80 (1H, dd, J=5,8Hz), 5.16 (1H, d, J=5 Hz), 4.78 (2H, AB_(q), J=14 Hz), 3.95 (3H, s),3.57 (2H, AB_(q), J=18 Hz).

EXAMPLE 16

A solution of7-[2-methoxyimino-2-{2-(2,2,2-trifluoroacetamido)-1,3-thiazol-4-yl}acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (0.3 g.) in a 0.1N aqueous solution of sodiumhydroxide (10.5 ml.) was warmed at 45° C. for 6 hours. Water (15 ml.)and ethyl acetate (30 ml.) were added to the reaction mixture and theresulting mixture was adjusted to pH 3.5 with 10% hydrochloric acid. Theaqueous layer was separated, washed with ethyl acetate and adjusted topH 5.0 with an aqueous solution of sodium bicarbonate. The aqueoussolution was subjected to column chromatography on Amberlite XAD-2 (20ml.)(prepared by Rohm & Haas Co.) using 10% ethanol as developingsolvent. The eluate containing object compound was collected andlyophilized to give7-[2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (0.12 g.).

I.R. spectrum (Nujol) 3200, 1765, 1600 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.51 (1H, d, J=8.5 Hz), 7.22 (2H,broad s), 6.72 (1H, s), 5.59 (1H, dd, J=5,8.5 Hz), 5.00 (1H, d, J=5 Hz),4.35 (2H, AB_(q), J=12 Hz), 3.90 (3H, s), 3.81 (3H, s), 3.55 (2H,AB_(q), J=18 Hz).

EXAMPLE 17

Trifluoroacetic acid (3 ml) was added under ice-cooling to7-[2-methoxyimino-2-(2-t-pentyloxycarbonylamino-1,3-thiazol-4-yl)acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (0.5 g) and the mixture was stirred for 30 minutes atambient temperature. To the mixture was added ether and precipitatingpowder was collected by filtration and dissolved in a mixture of water(20 ml) and an 1N aqueous solution of sodium hydroxide to adjust to pH12 to 13. The solution was adjusted to pH 4.6 with 10% hydrochloricacid, washed with ethyl acetate and methylene chloride. Excess methylenechloride in the aqueous layer was throughly removed by bubbling ofnitrogen gas. The aqueous layer was adjusted to pH 2 with stirring andice-cooling to precipitate powder. The powder was collected byfiltration and dried to give7-[2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (0.128 g).

I.R. spectrum (Nujol) 3400-3150, 1770, 1670, 1625 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.66 (1H, d, J=8 Hz), 7.34 (2H, broads), 6.76 (1H, s), 5.78 (2H, dd, J=5, 8 Hz), 5.16 (1H, d, J=5 Hz), 4.40(2H, ABq, J=14 Hz), 3.85 (3H, s), 3.70 (2H, ABq, J=17 Hz), 2.68 (3H, s).

EXAMPLE 18

Trifluoroacetic acid (4 ml.) and anisole (2 ml.) were added underice-cooling to7-[2-allyloxyimino-2-(2-t-pentyloxycarbonylamino-1,3-thiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (0.9 g.) and the mixture was stirred for 40 minutes atambient temperature. The reaction mixture was post-treated according toa similar manner to that of Example 17 to give7-[2-allyloxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (0.425 g.).

I.R. spectrum (Nujol) 3100-3400, 1775, 1660, 1625 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.70 (1H, d, J=8 Hz), 6.80 (1H, s),6.30-5.60 (2H, m), 5.24 (2H, dd, J=8, 16 Hz), 5.15 (1H, d, J=5 Hz), 4.63(2H, d, J=5 Hz), 4.32 (2H, AB_(q), J=12 Hz), 3.94 (3H, s), 3.70 (2H,AB_(q), J=17 Hz).

EXAMPLE 19

Disodium hydrogen phosphate (0.26 g) was added to a suspension of7-[2-methoxyimino-2-{2-(2,2,2-trifluoroacetamido)-1,3-thiazol-4-yl}acetamido]cephalosporanicacid(syn isomer) (1 g) in water (15 ml). A saturated aqueous solution ofdisodium hydrogen phosphate was further added thereto to adjust the pHvalue of the mixture at 6. The resulting mixture was stirred for 23hours at ambient temperature. The reaction mixture was adjusted to pH 4under ice-cooling with 10% hydrochloric acid, washed with ethyl acetateand adjusted to pH 2.5 with 10% hydrochloric acid. Precipitatingcrystals were collected by filtration, washed with cold water and driedto give7-[2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]cephalosporanicacid (syn isomer) (0.18 g), mp 227° C. (dec.).

I.R. spectrum (Nujol) 3300-3350, 1780, 1740, 1670 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.6 (1H, d, J=8 Hz), 6.8 (1H, s), 5.8(1H, dd, J=5,8 Hz), 5.2 (1H, d, J=5 Hz), 4.87 (2H, ABq, J=13 Hz), 3.89(3H, s), 3.6 (2H, broad s), 2.08 (3H, s).

EXAMPLE 20

7-[2-Methoxyimino-2-{2-(2,2,2-trifluoroacetamido)-1,3-thiazol-4-yl}acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (23 g) was suspended in a solution of sodium acetatetrihydrate (74.8 g) in water (230 ml) and the suspension was stirred for15 hours at ambient temperature. The reaction mixture was adjusted to pH5.0 with conc. hydrochloric acid and insoluble material was filteredoff. The filtrate was adjusted to pH 2.5 and precipitating crystals werecollected by filtration and dried to give7-[2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (14 g), mp 172° to 175° C. (dec.).

I.R. spectrum (Nujol) 3300, 1770, 1665 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.80 (1H, d, J=8 Hz), 9.63 (1H, s),6.95 (1H, s), 6.8 (2H, m), 5.82 (1H, dd, J=5, 8 Hz), 5.22 (1H, d, J=5Hz), 4.48 (2H, ABq, J=15 Hz), 3.97 (3H, s), 3.76 (2H, ABq, J=18 Hz).

EXAMPLE 21

7-[2-Methoxyimino-2-{2-(2,2,2-trifluoroacetamido)-1,3-thiazol-4-yl}acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylicacid (syn isomer) (3.5 g.) was suspended in a solution of sodium acetatetrihydrate (12.2 g.) in water (30 ml.). The mixture was stirred for 15hours at ambient temperature. The reaction mixture was saturated withsodium chloride and adjusted to pH 5.0 with conc. hydrochloric acid withstirring and ice-cooling. Precipitating insoluble material was filteredoff. The filtrate was adjusted to pH 3.0 with conc. hydrochloric acidand further adjusted to pH 1.5 with 10% hydrochloric acid. Precipitateswere collected by filtration and dried to give7-[2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylicacid (syn isomer) (2.1 g.), mp 210° to 220° C. (dec.).

I.R. spectrum (Nujol) 3250, 1765, 1650 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.64 (1H, d, J=8 Hz), 7.4 (2H, m),6.79 (1H, s), 6.60 (2H, m), 5.77 (1H, dd, J=5,8 Hz), 5.16 (1H, d, J=5Hz), 4.75 (2H, AB_(q), J=12 Hz), 3.87 (3H, s), 3.53 (2H, AB_(q), J=18Hz).

EXAMPLE 22

Conc. hydrochloric acid (10.4 ml.) was added with stirring at ambienttemperature to a suspension of7-[2-methoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acetamido]cephalosporanicacid (syn isomer) (48.35 g.) in methanol (725 ml.). After stirring for 3hours at ambient temperature, the reaction mixture was adjusted to pH4.5 with aqueous solution of ammonia and methanol was distilled off. Tothe residue was added water (100 ml.). The mixture was adjusted to pH6.5 with an aqueous solution of sodium bicarbonate, and insolublematerial was collected by filtration to give6-[2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-5a,6-dihydro-3H,7H-azeto[2,1-b]furo[3,4-d][1,3]-thiazine-1,7(4H)dione(syn isomer) (6.5 g.). The filtrate was adjusted to pH 4.5 with aceticacid, adsorbed by Diaion HP-20 resin (Trademark: prepered by MitsubishiChemical Industries Ltd.) (600 ml.), washed with water (2 l.) and theneluted with 25% aqueous solution of isopropyl alcohol. Eluatescontaining the object compounds were collected and cooled after additionof isopropyl alcohol (1/3 volume of the eluates). Precipitates werecollected by filtration, washed with isopropyl alcohol and dried to give7-[2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]cephalosporanicacid (syn isomer) (10.4 g.). The mother liquor was concentrated underreduced pressure until crystals began to precipitate. To the residue wasadded isopropyl alcohol (2/3 volume of the residue). The mixture wascooled and precipitates were collected by filtration to give the sameobject compound (5.8 g.). Total yield (16.2 g.). This compound wasidentified with the compound obtained in the foregoing Examples by I.R.and N.M.R. spectra.

EXAMPLE 23

7-[2-Methoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (10.8 g.) was added to methanol (200 ml.), andphosphorus oxychloride (7.2 g.) was dropwise added thereto with stirringand ice-cooling at 2° to 9° C. After stirring for 1.5 hours at the sametemperature, the reaction mixture was concentrated under reducedpressure on a water bath of 25° to 28° C. to the volume of 100 ml. Tothe residue was added ether (300 ml.) with stirring and ice-cooling.Precipitates were collected by filtration and dried to give7-[2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid hydrochloride (syn isomer) (12.3 g.). This powder (12.3 g.) wassuspended in water (100 ml.) and dissolved by adjusting pH of thesuspension to 7.5 by addition of a saturated aqueous solution of sodiumbicarbonate. To the solution was added ethyl acetate (100 ml.), and themixture was adjusted to pH 2.5 with 10% hydrochloric acid. Precipitateswere collected by filtration, washed with cold water and dried to give7-[2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (6.1 g.). The aqueous layer in the mother liquor wasseparated and stirred under cooling after addition of sodium chloride.Precipitates were collected by filtration to give the same objectcompound (3.8 g.). Total yield (9.9 g.). This compound was identifiedwith the compound obtained in the foregoing Examples by I.R. and N.M.R.spectra.

EXAMPLE 24

The following compounds were obtained according to similar manners tothose of Examples 16 to 23.

(1)7-[2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-hydroxymethyl-3-cephem-4-carboxylicacid (syn isomer), mp 260° to 270° C. (dec.).

I.R. spectrum (Nujol) 3370, 3270, 1765, 1660, 1610, 1590, 1550 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.58 (1H, d, J=8 Hz), 6.76 (1H, s),5.75 (1H, dd, J=5, 8 Hz), 5.12 (1H, d, J=5 Hz), 4.27 (2H, broad s), 3.85(3H, s), 3.57 (2H, broad s).

(2)7-[2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylicacid (syn isomer), mp 210° to 220° C. (dec.).

I.R. spectrum (Nujol) 3250, 1765, 1650 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ)

ppm: 9.64 (1H, d, J=8 Hz), 7.4 (2H, m), 6.79 (1H, s), 6.60 (2H, m), 5.77(1H, dd, J=5, 8 Hz), 5.16 (1H, d, J=5 Hz), 4.75 (2H, ABq, J=12 Hz), 3.87(3H, s), 3.53 (2H, ABq, J=18 Hz).

(3)7-[2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-(4-methyl-4H-1,2,4-triazol-3-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 185° C. (dec.).

I.R. spectrum (Nujol) 3150-3350, 1770, 1710, 1660, 1630 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.61 (1H, d, J=8 Hz), 8.69 (1H, s),6.73 (1H, s), 5.72 (1H, dd, J=4, 8 Hz), 5.1 (1H, d, J=4 Hz), 4.1 (2H,ABq, J=13 Hz), 3.87 (3H, s), 3.65 (2H, broad s), 3.59 (3H, s).

(4)6-[2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-5a,6-dihydro-3H,7H-azeto[2,1-b]furo[3,4-d][1,3]thiazine-1,7(4H)-dione(syn isomer), mp 210° to 215° C. (dec.).

I.R. spectrum (Nujol) 3270, 1780, 1740, 1655, 1610, 1525 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.70 (1H, d, J=8 Hz), 7.26 (2H, broads), 6.77 (1H, s), 5.93 (1H, dd, J=5, 8 Hz), 5.16 (1H, d, J=5 Hz), 5.05(2H, broad s), 3.85 (3H, s), 3.81 (2H, broad s).

(5)7-[2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-[1-(2-dimethylaminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. spectrum (Nujol) 1765 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.56 (1H, d, J=8 Hz), 6.75 (1H, s),5.75 (1H, m), 5.10 (1H, d, J=4 Hz), 4.58 (2H, broad s), 4.32 (2H, broads), 3.82 (3H, s), 3.68 (2H, broad s), 3.20 (2H, broad s), 2.50 (6H, s).

EXAMPLE 25

A suspension of7-[2-methoxyimino-2-{2-(2,2,2-trifluoroacetamido)-1,3-thiazol-4-yl}acetamido]cephalosporanicacid (syn isomer) (2.76 g) and 4-methyl-4H-1,2,4-triazole-3-thiol (0.63g) in pH 6.4 phosphate buffer solution (50 ml) was adjusted to pH 6.4with sodium bicarbonate and stirred for 6 hours at 65° to 70° C. Thereaction mixture was cooled and ethyl acetate was added thereto. Themixture was adjusted to pH 5 with 10% hydrochloric acid and washed withethyl acetate. The aqueous layer was treated with activated charcoal andadjusted to pH 2.7 with 10% hydrochloric acid with stirring andice-cooling. Precipitating crystals were collected by filtration, washedwith cold water and dried to give7-[2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-(4-methyl-4H-1,2,4-triazol-3-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (0.7 g), mp 185° C. (dec.).

I.R. spectrum (Nujol) 3150-3350, 1770, 1710, 1660, 1630 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.61 (1H, d, J=8 Hz), 8.69 (1H, s),6.73 (1H, s), 5.72 (1H, dd, J=4, 8 Hz), 5.1 (1H, d, J=4 Hz), 4.1 (2H,ABq, J=13 Hz), 3.87 (3H, s), 3.59 (3H, s), 3.65 (2H, broad s).

EXAMPLE 26

The following compounds were obtained according to a similar manner tothat of Example 25.

(1)7-[2-Methoxyimino-2-(2-methyl-1,3-thiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. spectrum (Nujol) 1780, 1710, 1675 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ)

ppm: 9.65 (1H, d, J=10 Hz), 7.66 (1H, s), 5.81 (1H, dd, J=5, 10 Hz),5.15 (1H, d, J=5 Hz), 4.31 (2H, ABq, J=13 Hz), 3.93 (3H, s), 3.90 (3H,s), 3.70 (2H, ABq, J=16 Hz), 2.65 (3H, s).

(2)7-[2-Methoxyimino-2-(2-mesylimino-3-methyl-2,3-dihydro-1,3-thiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. spectrum (Nujol) 3250, 1780, 1718, 1675 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.80 (1H, d, J=8 Hz), 7.08 (1H, s),5.80 (1H, dd, J=5, 8 Hz), 5.18 (1H, d, J=5 Hz), 4.34 (2H, ABq, J=13 Hz),3.99 (3H, s), 3.96 (3H, s), 3.72 (2H, ABq, J=17 Hz), 3.66 (3H, s), 2.98(3H, s).

(3)7-[2-Methoxyimino-2-(2-mesylamino-1,3-thiazol-4-yl)-acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. spectrum (Nujol) 3300-3150, 1780, 1710, 1670 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.84 (1H, d, J=8 Hz), 6.97 (1H, s),5.76 (1H, dd, J=5, 8 Hz), 5.12 (1H, d, J=5 Hz), 4.33 (2H, ABq, J=13 Hz),3.93 (6H, s), 3.74 (2H, ABq, J=17 Hz), 2.96 (3H, s).

(4)7-[2-Methoxyimino-2-(2-oxo-2,3-dihydro-1,3-thiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. spectrum (Nujol) 1780, 1665 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 11.67 (1H, s), 9.83 (1H, d, J=8 Hz),6.61 (1H, s), 5.80 (1H, dd, J=5.5, 8 Hz), 5.17 (1H, d, J=5.5 Hz), 4.37(2H, broad s), 4.00 (3H, s), 3.96 (3H, s), 3.75 (2H, broad s).

(5)7-[2-Allyloxyimino-2-(2-mesylamino-1,3-thiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. spectrum (Nujol) 3100-3300, 1780, 1720, 1675 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.90 (1H, d, J=8 Hz), 7.00 (1H, s),6.07-5.63 (2H, m), 5.43 (2H, d, J=8 Hz), 5.18 (1H, d, J=5 Hz), 4.70 (2H,d, J=5 Hz), 4.37 (2H, broad s), 3.98 (3H, s), 3.75 (2H, broad s), 3.00(3H, s).

(6)7-[2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. spectrum (Nujol) 3200, 1765, 1600 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.51 (1H, d, J=8.5 Hz), 7.22 (2H,broad s), 6.72 (1H, s), 5.59 (1H, dd, J=5, 8.5 Hz), 5.00 (1H, d, J=5Hz), 4.35 (2H, ABq, J=12 Hz), 3.90 (3H, s), 3.81 (3H, s), 3.55 (2H, ABq,J=18 Hz).

(7)7-[2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. spectrum (Nujol) 3400-3150, 1770, 1670, 1625 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.66 (1H, d, J=8 Hz), 7.34 (2H, broads), 6.76 (1H, s), 5.78 (2H, dd, J=5, 8 Hz), 5.16 (1H, d, J=5 Hz), 4.40(2H, ABq, J=14 Hz), 3.85 (3H, s), 3.70 (2H, ABq, J=17 Hz), 2.68 (3H, s).

(8)7-[2-Allyloxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. spectrum (Nujol) 3100-3400, 1775, 1660, 1625 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.70 (1H, d, J=8 Hz), 6.80 (1H, s),6.30-5.60 (2H, m), 5.24 (2H, dd, J=8, 16 Hz), 5.15 (1H, d, J=5 Hz), 4.63(2H, d, J=5 Hz), 4.32 (2H, ABq, J=12 Hz), 3.94 (3H, s), 3.70 (2H, ABq,J=17 Hz).

(9)7-[2-Methoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 145° to 147° C. (dec.).

I.R. spectrum (Nujol) 3150-3400, 1780, 1725, 1680, 1640 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 12.58 (1H, broad s), 9.70 (1H, d, J=8Hz), 9.58 (1H, s), 8.50 (1H, s), 7.40 (1H, s), 5.82 (1H, dd, J=5, 8 Hz),5.17 (1H, d, J=5 Hz), 4.43 (2H, ABq, J=13 Hz), 3.88 (3H, s), 3.70 (2H,broad s).

(10)7-[2-Methoxyimino-2-(2-acetamido-1,3-thiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 171° to 173° C. (dec.).

I.R. spectrum (Nujol) 3500, 3250, 1780, 1720, 1670 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.65 (1H, d, J=8 Hz), 7.3 (1H, s),5.8 (1H, dd, J=5, 8 Hz), 5.15 (1H, d, J=5 Hz), 4.35 (2H, broad s), 3.97(3H, s), 3.9 (3H, s), 3.75 (2H, broad s), 2.15 (3H, s).

(11)7-[2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 172° to 175° C. (dec.).

I.R. spectrum (Nujol) 3300, 1770, 1665 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.80 (1H, d, J=8 Hz), 9.63 (1H, s),6.95 (1H, s), 6.8 (2H, m), 5.82 (1H, dd, J=5, 8 Hz), 5.22 (1H, d, J=5Hz), 4.48 (2H, ABq, J=15 Hz), 3.97 (3H, s), 3.76 (2H, ABq, J=18 Hz).

(12)7-[2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-[1-(2-dimethylaminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. spectrum (Nujol) 1765 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.56 (1H, d, J=8 Hz), 6.75 (1H, s),5.75 (1H, m), 5.10 (1H, d, J=4 Hz), 4.58 (2H, broad s), 4.32 (2H, broads), 3.82 (3H, s), 3.68 (2H, broad s), 3.20 (2H, broad s), 2.50 (6H, s).

(13)7-[2-Methoxyimino-2-(2-ethoxycarbonylamino-1,3-thiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. spectrum (Nujol) 3200, 1775, 1720, 1680, 1660 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 11.9 (1H, m), 9.70 (1H, d, J=10 Hz),9.55 (1H, s), 7.31 (1H, s), 5.80 (1H, dd, J=5,10 Hz), 4.44 (2H, AB_(q),J=16 Hz), 4.22 (2H, q, J=7 Hz), 3.89 (3H, s), 3.72 (2H, AB_(q), J=16Hz), 1.23 (3H, t, J=7 Hz).

(14)7-[2-Methoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. spectrum (Nujol) 3200-3300, 2600, 1780, 1720, 1690, 1675 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 12.60 (1H, broad s), 9.70 (1H, d, J=8Hz), 8.50 (1H, s), 7.44 (1H, s), 5.88 (1H, dd, J=5,8 Hz), 5.19 (1H, d,J=5 Hz), 4.25 (2H, AB_(q), J=13 Hz), 3.95 (3H, s), 3.85 (3H, s), 3.65(2H, AB_(q), J=18 Hz).

(15)7-[2-Methoxyimino-2-(3-hydroxyphenyl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. spectrum (Nujol) 3250, 1770, 1725, 1670 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.76 (1H, d, J=8 Hz), 6.7-7.40 (4H,m), 5.86 (1H, dd, J=5, 8 Hz), 5.18 (1H, d, J=5 Hz), 4.34 (2H, ABq, J=13Hz), 3.92 (6H, s), 3.72 (2H, ABq, J=17 Hz).

(16)7-[2-t-Butoxycarbonylmethoxyimino-2-(3-chloro-4-hydroxyphenyl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), powder.

(17)7-[2-Carboxy-methoxyimino-2-(3-chloro-4-hydroxyphenyl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 145° to 148° C. (dec.).

I.R. spectrum (Nujol) 3400, 3200-3300, 2500-2600, 1780, 1720, 1670, 1600cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.70 (1H, d, J=8 Hz), 7.50 (1H, d,J=2 Hz), 7.45 (1H, dd, J=2, 8 Hz), 7.10 (1H, d, J=8 Hz), 5.90 (1H, q,J=5 Hz), 5.22 (1H, d, J=5 Hz), 4.70 (2H, s), 4.35 (2H, ABq, J=13 Hz),3.95 (3H, s), 3.75 (2H, ABq, J=18 Hz).

(18)7-[2-(1-t-Butoxycarbonylethoxyimino)-2-(3-chloro-4-hydroxyphenyl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), powder.

(19)7-[2-(1-Carboxyethoxyimino)-2-(3-chloro-4-hydroxyphenyl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 147° to 151° C. (dec.).

I.R. spectrum (Nujol) 3500, 3250, 2500-2600, 1780, 1730, 1660, 1630,1600 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.62 (1H, d, J=8 Hz), 7.46 (1H, d,J=2 Hz), 7.34 (1H, dd, J=2, 8 Hz), 7.04 (1H, d, J=8 Hz), 5.90 (1H, q,J=5 Hz), 5.22 (1H, d, J=5 Hz), 4.73 (1H, q, J=6 Hz), 4.33 (2H, ABq, J=13Hz), 4.00 (3H, s), 3.73 (2H, ABq, J=18 Hz), 1.37 (3H, d, J=6 Hz).

(20)7-[2-Methoxyimino-2-(3-hydroxyphenyl)acetamido]-3-(4H-1,2,4-triazol-3-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. spectrum (Nujol) 3250, 1775, 1710, 1665 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.67 (1H, d, J=8 Hz), 8.40 (1H, s),6.70-7.43 (4H, m), 5.82 (1H, dd, J=5, 8 Hz), 5.13 (1H, d, J=5 Hz), 4.18(2H, ABq, J=13 Hz), 3.90 (3H, s), 3.67 (2H, broad s).

(21)7-[2-Methoxyimino-2-(3-hydroxyphenyl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. spectrum (Nujol) 3250, 1780, 1720, 1670 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.78 (1H, d, J=8 Hz), 9.55 (1H, s),6.70-7.40 (4H, m), 5.89 (1H, dd, J=5, 8 Hz), 5.22 (1H, d, J=5 Hz), 4.46(2H, ABq, J=13 Hz), 3.92 (3H, s), 3.76 (2H, ABq, J=18 Hz),

(22)7-[2-Methoxyimino-2-(3-hydroxyphenyl)acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. spectrum (Nujol) 3250, 1780, 1720, 1670 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.72 (1H, d, J=8 Hz), 6.62-7.40 (4H,m), 5.94 (1H, dd, J=5, 8 Hz), 5.18 (1H, d, J=5 Hz), 4.18 (2H, ABq, J=13Hz), 3.89 (3H, s), 3.70 (2H, ABq, J=17 Hz), 2.65 (3H, s).

(23)7-[2-Methoxyimino-2-(3-methoxyphenyl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. spectrum (Nujol) 3250, 1780, 1720, 1670 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.78 (1H, d, J=8 Hz), 6.95-7.54 (4H,m), 5.94 (1H, dd, J=5, 8 Hz), 5.18 (1H, d, J=5 Hz), 4.12 (2H, ABq, J=13Hz), 3.92 (6H, s), 3.76 (3H, s), 3.72 (2H, ABq, J=18 Hz).

(24)7-[2-Methoxyimino-2-(4-hydroxyphenyl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. spectrum (Nujol) 3250, 1780, 1720, 1670 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.70 (1H, d, J=8 Hz), 7.44 (2H, d,J=8 Hz), 6.84 (2H, d, J=8 Hz), 5.86 (1H, dd, J=5, 8 Hz), 5.18 (1H, d,J=5 Hz), 4.34 (2H, ABq, J=13 Hz), 3.93 (3H, s), 3.87 (3H, s), 3.74 (2H,ABq, J=18 Hz).

(25)7-[2-Methoxyimino-2-(3-chloro-4-hydroxyphenyl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 145° to 148° C. (dec.).

I.R. spectrum (Nujol) 3500, 3250, 2500-2600, 1780, 1720, 1655, 1625,1600 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 10.80 (1H, broad s), 9.68 (1H, d, J=2Hz), 7.46 (1H, d, J=2 Hz), 7.32 (1H, q, J=2, 8 Hz), 7.00 (1H, d, J=8Hz), 5.80 (1H, q, J=5 Hz), 5.16 (1H, d, J=5 Hz), 4.28 (2H, ABq, J=13Hz), 3.92 (3H, s), 3.87 (3H, s), 3.72 (2H, ABq, J=18 Hz).

(26)7-[2-Methoxyimino-2-(3-chloro-4-methoxyphenyl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 143° to 145° C. (dec.).

I.R. spectrum (Nujol) 3300, 2500-2600, 1785, 1730, 1670, 1630, 1600 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.76 (1H, d, J=8 Hz), 7.56 (1H, d,J=2 Hz), 7.48 (1H, dd, J=2, 8 Hz), 7.22 (1H, d, J=8 Hz), 5.84 (1H, q,J=5 Hz), 5.18 (1H, d, J=5 Hz), 4.27 (2H, ABq, J=13 Hz), 3.90 (6H, s),3.88 (3H, s), 3.70 (2H, ABq, J=18 Hz).

(27)7-[2-Methoxyimino-2-(3-nitro-4-hydroxyphenyl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 149° to 152° C. (dec.).

I.R. spectrum (Nujol) 3400-3450, 3200, 2500-2600, 1780, 1720, 1660,1620, 1600, 1535, 1350 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.72 (1H, d, J=8 Hz), 7.97 (1H, d,J=2 Hz), 7.72 (1H, dd, J=2, 8 Hz), 7.21 (1H, d, J=8 Hz), 5.82 (1H, q,J=5 Hz), 5.16 (1H, d, J=5 Hz), 4.3 (2H, ABq, J=13 Hz), 3.92 (3H, s),3.87 (3H, s), 3.72 (2H, ABq, J=18 Hz).

(28)7-[2-Allyloxyimino-2-(3-chloro-4-hydroxyphenyl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 163° to 165° C. (dec.).

I.R. spectrum (Nujol) 3200-3300, 2500-2600, 1780, 1720, 1670, 1600 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.70 (1H, d, J=8 Hz), 7.40 (1H, d,J=2 Hz), 7.30 (1H, dd, J=2, 8 Hz), 6.95 (1H, d, J=8 Hz), 5.80 (2H, m),5.30 (2H, d, J=8 Hz), 5.10 (1H, d, J=5 Hz), 4.60 (2H, d, J=5 Hz), 4.27(2H, ABq, J=13 Hz), 3.85 (3H, s), 3.65 (2H, ABq, J=18 Hz).

(29)7-[2-Allyloxyimino-2-(3-hydroxyphenyl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 149° to 152° C. (dec.).

I.R. spectrum (Nujol) 3250-3350, 2550-2600, 1780, 1730, 1670, 1650, 1600cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.70 (1H, d, J=8 Hz), 7.2-6.8 (4H,m), 6.1-5.8 (2H, m), 5.35 (2H, d, J=8 Hz), 5.17 (1H, d, J=5 Hz), 4.7(2H, d, J=5 Hz), 4.17 (2H, ABq, J=13 Hz), 3.93 (3H, s), 3.75 (2H, ABq,J=18 Hz).

(30)7-[2-(3-Hydroxy-4-bromobenzyloxyimino)-2-(4-hydroxyphenyl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), powder.

I.R. spectrum (Nujol) 3150, 1780, 1720, 1670 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.60 (1H, d, J=8 Hz), 6.72-7.52 (7H,m), 5.80 (1H, dd, J=4, 8 Hz), 5.15 (1H, d, J=4 Hz), 5.00 (2H, s), 4.28(2H, ABq, J=13 Hz), 3.90 (3H, s), 3.65 (2H, ABq, J=18 Hz).

(31)7-[2-(2-Thienylmethoxyimino)-2-(4-hydroxyphenyl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), powder.

I.R. spectrum (Nujol) 3200-3300, 1780, 1720, 1660 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.77 (1H, d, J=8 Hz), 6.7-7.7 (7H,m), 5.83 (1H, dd, J=5, 8 Hz), 5.29 (2H, s), 5.15 (1H, d, J=5 Hz), 4.3(2H, ABq, J=13 Hz), 3.92 (3H, s), 3.72 (2H, ABq, J=18 Hz).

(32)7-[2-Ethoxyimino-2-(3-chloro-4-hydroxyphenyl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), colorless powder, mp 153° to 156° C. (dec.)

I.R. spectrum (Nujol) 3450, 3250, 2550-2600, 1780, 1725, 1665, 1630,1600 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.71 (1H, d, J=8 Hz), 7.50 (1H, d,J=2 Hz), 7.36 (1H, dd, J=2, 8 Hz), 7.03 (1H, d, J=8 Hz), 5.83 (1H, q,J=5 Hz), 5.17 (1H, d, J=5 Hz), 4.33 (2H, ABq, J=13 Hz), 4.17 (2H, q, J=7Hz), 3.97 (3H, s), 3.73 (2H, ABq, J=18 Hz), 1.25 (3H, t, J=7 Hz).

(33)7-[2-Allyloxyimino-2-(3-methoxyphenyl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), powder, mp 135° to 138° C. (dec.).

I.R. spectrum (Nujol) 3300, 2600, 1785, 1730, 1670, 1645, 1600 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.82 (1H, d, J=8 Hz), 7.0-7.45 (4H,m), 5.8-6.2 (2H, m), 5.36 (2H, t, J=10 Hz), 5.21 (1H, d, J=5 Hz), 4.72(2H, d, J=5 Hz), 4.36 (2H, ABq, J=13 Hz), 3.95 (3H, s), 3.91 (3H, s),3.87 (2H, ABq, J=18 Hz).

(34)7-[2-Ethoxyimino-2-(3-hydroxyphenyl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), yellow powder, mp 145° to 148° C. (dec.).

I.R. spectrum (Nujol) 3450, 3250, 2500-2600, 1775, 1720, 1665, 1620,1600 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.70 (1H, d, J=8 Hz), 6.8-7.4 (4H,m), 5.90 (1H, q, J=5 Hz), 5.20 (1H, d, J=5 Hz), 4.36 (2H, ABq, J=13 Hz),4.20 (2H, q, J=7 Hz), 4.00 (3H, s), 3.76 (2H, ABq, J=18 Hz), 1.33 (3H,t, J=7 Hz).

(35)7-[2-Ethoxyimino-2-(3-methoxyphenyl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), pale yellow powder, mp 140° to 143° C. (dec.).

I.R. spectrum (Nujol) 3300, 2500-2600, 1785, 1730, 1670, 1630, 1600 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.71 (1H, d, J=8 Hz), 6.9-7.5 (4H,m), 5.90 (1H, q, J=5 Hz), 5.17 (1H, d, J=5 Hz), 4.33 (2H, ABq, J=13 Hz),4.20 (2H, q, J=7 Hz), 3.95 (3H, s), 3.85 (3H, s), 3.75 (2H, ABq, J=18Hz), 1.30 (3H, t, J=7 Hz).

(36)7-[2-Allyloxyimino-2-(3-chloro-4-methoxyphenyl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), pale yellow powder, mp 153° to 156° C. (dec.).

I.R. spectrum (Nujol) 3250, 2600, 1780, 1720, 1670, 1645, 1630, 1600cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.65 (1H, d, J=8 Hz), 7.27 (1H, d,J=2 Hz), 7.20 (1H, dd, J=2, 8 Hz), 7.09 (1H, d, J=8 Hz), 5.85-6.15 (2H,m), 5.15 (2H, t, J=9 Hz), 5.05 (1H, d, J=5 Hz), 4.60 (2H, d, J=5 Hz),4.15 (2H, ABq, J=13 Hz), 3.95 (3H, s), 3.90 (3H, s), 3.47 (2H, ABq, J=18Hz).

(37)7-[2-Phenylthiomethoxyimino-2-(3-hydroxyphenyl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. spectrum (Nujol) 3300, 1760, 1660, 1600, 1580, 1520 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.7 (1H, d, J=8 Hz), 7.7-6.7 (9H, m),5.8-5.4 (3H, broad s), 5.06 (1H, d, J=5Hz), 4.33 (2H, broad s), 3.9 (3H,s), 3.56 (2H, broad s).

(38)7-[2-Methoxyimino-2-(3-mesylaminophenyl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 155° C. (dec.).

I.R. spectrum (Nujol) 3300, 1780, 1730, 1670 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.98 (1H, s), 9.81 (1H, d, J=9 Hz),9.62 (1H, s), 5.90 (1H, dd, J=5,9 Hz), 5.24 (1H, d, J=5 Hz), 4.49 (2H,ABq, J=14 Hz), 3.98 (3H, s), 3.77 (2H, broad s), 2.96 (3H, s).

(39)7-[2-Methoxyimino-2-(3-carbamoyloxyphenyl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. spectrum (Nujol) 3450, 3300, 3200, 1780, 1725, 1670, 1620, 1590,1520 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.77 (1H, d, J=7 Hz), 7.6-6.8 (6H,m), 5.83 (1H, dd, J=4, 7 Hz), 5.17 (1H, d, J=4 Hz), 4.31 (2H, ABq, J=14Hz), 3.96 (6H, s), 3.72 (2H, broad s).

(40)7-[2-Methoxyimino-2-(3-carbamoyloxyphenyl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. spectrum (Nujol) 3250, 1780, 1735, 1675, cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.81 (1H, d, J=8 Hz), 9.62 (1H, s),6.7-7.58 (4H, m), 5.8 (1H, dd, J=5, 8 Hz), 5.2 (1H, d, J=5 Hz), 4.25,4.63(2H, ABq, J=14 Hz), 3.9 (3H, s), 3.7 (2H, broad s).

(41)7-[2-Methoxyimino-2-(3-acetoxyphenyl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. spectrum (Nujol) 3250, 1780, 1740, 1720, 1680 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.86 (1H, d, J=8 Hz), 9-61 (1H, s),7.00-7.65 (4H, m), 5.84 (1H, dd, J=5, 8 Hz), 5.2 (1H, d, J=5 Hz),4.25-4.63 (2H, ABq, J=14 Hz), 3.92 (3H, s), 3.53, 3.86 (2H, ABq, J=19Hz), 2.3 (3H, s).

(42)7-[2-(3-Phenylallyloxyimino)-2-(3-hydroxyphenyl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 138° to 142° C. (dec.).

I.R. spectrum (Nujol) 3300-3400, 2600, 1780, 1720, 1665, 1600 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.80 (1H, d, J=8 Hz), 6.4-7.4 (11H,m), 5.85 (1H, dd, J=5, 8 Hz), 5.20 (1H, d, J=5 Hz), 4.83 (2H, d, J=5Hz), 4.32 (2H, ABq, J=15 Hz), 3.95 (3H, s), 3.68 (2H, ABq, J=18 Hz).

(43)7-[2-Methoxyimino-2-(4-dimethylaminophenyl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 88° C. (dec.).

I.R. spectrum (Nujol) 3250, 1780, 1730, 1680, 1610 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.63 (1H, d, J=8 Hz), 7.40 (2H, d,J=8 Hz), 6.73 (2H, d, J=8 Hz), 5.83 (1H, dd, J=5, 8 Hz), 5.17 (1H, d,J=5 Hz), 4.33 (2H, ABq, J=13 Hz), 3.97 (3H, s), 3.87 (3H, s), 3.73 (2H,broad s), 3.00 (6H, s).

(44)7-[2-Methoxyimino-2-(3-hydroxyphenyl)acetamido]-3-[1-(2-dimethylaminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. spectrum (Nujol) 1765 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.67 (1H, d, J=9 Hz), 6.72-7.36 (4H,m), 5.78 (1H, dd, J=5, 9 Hz), 5.12 (1H, d, J=5 Hz), 4.55 (2H, broad s),4.30 (2H, broad s), 3.90 (3H, s), 3.40-3.80 (2H, m), 3.14 (2H, broad s),2.48 (6H, s).

(45)7-[2-{2-(2-Hydroxyphenoxy)ethoxyimino}-2-(3-hydroxyphenyl)-acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. spectrum (Nujol) 3270, 1780, 1725, 1670, 1560 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 6.5-7.4 (8H, m), 5.86(1H, dd, J=5, 8Hz), 5.14(1H, d, J=5 Hz), 4.0-4.6 (6H, m), 3.92(3H, s), 3.52, 3.70(2H,AB_(q), J=7 Hz).

EXAMPLE 27

A solution of7-[2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-hydroxymethyl-3-cephem-4-carboxylicacid (syn isomer) (0.3 g) in a mixture of acetone (3 ml) and water (1.5ml) was adjusted to pH 2 with 6N hydrochloric acid and stirred for 4hours at ambient temperature. After the acetone was distilled off, tothe residue was added water (1 ml). The mixture was adjusted to pH 7with a saturated aqueous solution of sodium bicarbonate and ice-cooledfor 1 hour. Precipitating crystals were collected by filtration, washedwith water and dried to give6-[2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-5a,6-dihydro-3H,7H-azeto[2,1-b]furo[3,4-d][1,3]-thiazine-1,7(4H)-dione (syn isomer)(0.23 g), mp 210° to 215° C. (dec.).

I.R. spectrum (Nujol) 3270, 1780, 1740, 1655, 1610, 1525 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.70 (1H, d, J=8 Hz), 7.26 (2H, broads), 6.77 (1H, s), 5.93 (1H, dd, J=5, 8 Hz), 5.16 (1H, d, J=5 Hz), 5.05(2H, broad s), 3.85 (3H, s), 3.81 (2H, broad s).

EXAMPLE 28

The following compound was obtained according to a similar manner tothat of Example 27.

6-[2-methoxyimino-2-(3-hydroxyphenyl)acetamido]-5a,6-dihydro-3H,7H-azeto[2,1-b]furo[3,4-d][1,3]thiazine-1,7(4H)-dione(synisomer).

I.R. spectrum (Nujol) 3250, 1785, 1755, 1660, 1600, 1570, 1540 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.83 (1H, d, J=8 Hz), 7.5-6.75 (4H,m), 6.02 (1H, dd, J=5, 8 Hz), 5.21 (1H, d, J=5 Hz), 5.07 (2H, broad s),3.95 (3H, s), 3.84 (2H, broad s).

EXAMPLE 29

7-[2-Methoxyimino-2-{2-(2,2,2-trifluoroacetamido)-1,3-thiazol-4-yl}acetamido]-3-hydroxymethyl-3-cephem-4-carboxylicacid (syn isomer) (1.0 g.) was dissolved in a mixture ofdimethylformamide (6 ml.) and acetone (30 ml.). Jones reagent (1.25ml.), which was prepared from conc. sulfuric acid (0.28 ml.), chromiumtrioxide (0.33 g.) and water (0.9 ml.), was dropwise added thereto over2 minutes with stirring and cooling at 0° to 2° C. After stirring for 20minutes at the same temperature, the reaction mixture was poured intoice-water (50 ml.). After acetone was distilled off, the residue wastwice extracted with ethyl acetate (50 ml.). The extracts were washedwith a saturated aqueous solution of sodium chloride and dried overmagnesium sulfate. The solvent was distilled off and the residue waspulverized with diisopropyl ether to give7-[2-methoxyimino-2-{2-(2,2,2-trifluoroacetamido)-1,3-thiazol-4-yl}-acetamido]-3-formyl-3-cephem-4-carboxylicacid (syn isomer) [or this compound can be represented as3-hydroxy-6-[2-methoxyimino-2-{2-(2,2,2-trifluoroacetamido)-1,3-thiazol-4-yl}acetamido]-5a,6-dihydro-3H,7H-azeto[2,1-b]furo[3,4-d][1,3]thiazine-1,7(4H)dione(syn isomer)](0.56 g.).

I.R. spectrum (Nujol) 3150, 1790, 1720, 1655, 1560, 1500 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.88 (1H, d, J=8 Hz), 7.60 (1H, s),6.30 (1H, d, J=6 Hz), 6.05 (1H, dd, J=5, 8 Hz), 5.23 (1H, d, J=5 Hz),3.96 (3H, s), 3.80 (2H, broad s).

EXAMPLE 30

The following compounds were obtained by conducting elimination reactionof protective group of amino on carbamoyl group according to a similarmanner to that of Example 3.

(1)7-[2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylicacid (syn isomer), mp 210° to 220° C. (dec.).

I.R. spectrum (Nujol) 3250, 1765, 1650 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.64 (1H, d, J=8 Hz), 7.4 (2H, m),6.79 (1H, s), 6.60 (2H, m), 5.77 (1H, dd, J=5, 8 Hz), 5.16 (1H, d, J=5Hz), 4.75 (2H, AB_(q), J=12 Hz), 3.87 (3H, s), 3.53 (2H, AB_(q), J=18Hz).

(2)7-[2-Methoxyimino-2-(2-formamido-1,3-thiazol-4-yl)-acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. spectrum (Nujol) 3300, 1780, 1705, 1680 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 12.50 (1H, broad s), 9.67 (1H, d, J=8Hz), 8.50 (1H, s), 7.43 (1H, s), 6.58 (2H, broad s), 5.80 (1H, dd, J=5,8 Hz), 5.16 (1H, d, J=5 Hz), 4.78 (2H, AB_(q), J=14 Hz), 3.95 (3H, s),3.57 (2H, AB_(q), J=18 Hz).

REFERENCE 1

Phosphorus pentachloride (3.3 g.) was added under ice-cooling to asuspension of 2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetic acid(syn isomer) (1.5 g.) in methylene chloride (30 ml.) and the mixture wasstirred for 30 minutes at ambient temperature. Methylene chloride wasdistilled off under reduced pressure and acetone was added to theresidue to give a suspension. On the other hand, a suspension of7-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (2.2 g.) in an aqueous solution of sodium bicarbonate (0.76 g. in50 ml. of water) was stirred for 10 minutes and acetone (50 ml.) wasadded thereto to give a solution. To the solution was dropwise added theabove obtained suspension containing acid chloride with stirring andice-cooling and keeping the solution at pH 7.5 to 8.5 with a 20% aqueoussolution of sodium carbonate. The mixture was stirred for 1 hour at 3°to 5° C. and pH 8.0. Acetone was distilled off under reduced pressureand the residue was adjusted to pH 7.4 with a saturated aqueous solutionof sodium bicarbonate and further adjusted to pH 4.5 with 10%hydrochloric acid with stirring and ice-cooling. Precipitates werefiltered off and the filtrate was saturated with sodium chloride,adjusted to pH 2.5 with 10% hydrochloric acid and stirred for 1 hour.Precipitates were collected by filtration, washed with water and driedto give7-[2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (a mixture of syn and anti isomers) (0.95 g.).

I.R. spectrum (Nujol) 3400, 1775, 1710, 1670, 1630 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.85 (1H, d, J=8 Hz), 9.50 (1H, d,J=8 Hz), 7.58 (1H, s), 6.87 (1H, s), 6.65 (4H, broad s), 5.77 (2H, m),5.15 (2H, d, J=5 Hz), 4.35 (4H, broad s), 4.06 (6H, s), 3.97 (6H, s),3.75 (4H, broad s).

REFERENCE 2

A suspension of phosphorus pentachloride (1.7 g.) in methylene chloride(20 ml.) was changed to a solution by stirring for 2 hours at ambienttemperature. 2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetic acid (synisomer) (0.8 g.) was added thereto at a time at ambient temperature andthe mixture was stirred. Methylene chloride was distilled off underreduced pressure and the residue was dissolved in acetone (20 ml.). Onthe other hand, 7-amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid(1.0 g.) was suspended in a solution of sodium bicarbonate (0.59 g.) inwater (20 ml.) and dissolved by adding acetone (10 ml.). To thissolution was dropwise added the above obtained solution containing acidchloride with stirring and ice-cooling and keeping the solution at pH7.5 to 8.5 with a 20% aqueous solution of sodium carbonate. Afterstirring for 1 hour at pH 8 under ice-cooling, an insoluble material wasfiltered off. Acetone was distilled off under reduced pressure from thefiltrate and an insoluble material was filtered off. The filtrate wasadjusted to pH 2.5 with 10% hydrochloric acid. Precipitates werecollected by filtration and dried to give7-[2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)-acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylicacid (a mixture of syn and anti isomers) (0.4 g.). The filtrate wassaturated with sodium chloride and stirred under ice-cooling to giveprecipitates. The precipitates were collected by filtration and dried togive the same object compound (0.3 g.). Total yield (0.7 g.).

I.R. spectrum (Nujol) 3400, 1775, 1705 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.71 (1H, d, J=8 Hz), 9.42 (1H, d,J=8 Hz), 7.70 (1H, s), 7.40 (4H, broad s), 7.00 (1H, s), 6.61 (4H, s),5.76 (2H, m), 5.16 (2H, d, J=4.5 Hz), 4.76 (4H, AB_(q), J=12 Hz), 3.98(3H, s), 3.89 (3H, s), 3.53 (4H, AB_(q), J=18 Hz).

REFERENCE 3

A mixture of dimethylformamide (0.22 g.) and phosphorus oxychloride(0.46 g.) was warmed for 1 hour at 40° C. The mixture was dissolved indry methylene chloride (20 ml.) and2-methoxyimino-2-(2-mesylimino-3-methyl-2,3-dihydro-1,3-thiazol-4-yl)aceticacid (anti isomer) (0.73 g.) was added thereto with stirring andice-cooling, after which the resulting mixture was stirred for 1.5 hoursunder ice-cooling. On the other hand,7-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (0.82 g.) was dissolved in a solution ofbis-(trimethylsilyl)acetamide (1.5 g.) in dry methylene chloride (20ml.). To this solution was added at -30° C. the above obtained methylenechloride solution, after which the mixture was stirred for 2 hours at-5° to -20° C. After distilling off methylene chloride at lowtemperature, water was added to the residue and the mixture wasextracted with ethyl acetate. The extract was washed with a sodiumchloride aqueous solution and water (50 ml.) was added thereto. Theresulting mixture was adjusted to pH 7 with an aqueous solution ofsodium bicarbonate and the aqueous layer was separated. The aqueouslayer was adjusted to pH 1.5, saturated with sodium chloride andextracted with ethyl acetate. The extract was washed with a sodiumchloride aqueous solution and dried over magnesium sulfate. The solventwas distilled off and the residue was pulverized by a mixture ofdiisopropyl ether and ether. The powder was collected by filtration anddried to give7-[2-methoxyimino-2-(2-mesylimino-3-methyl-2,3-dihydro-1,3-thiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (anti isomer) (1.0 g.). This powder (1.0 g.) was suspended in water(30 ml.) and dissolved by adjusting to pH 6 by an aqueous solution ofsodium bicarbonate. After removing the solvent by bubbling of nitrogengas, the aqueous solution was lyophilized to give sodium7-[2-methoxyimino-2-(2-mesylimino-3-methyl-2,3-dihydro-1,3-thiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate(anti isomer) (0.98 g.).

I.R. spectrum (KBr) 1760, 1675 cm⁻¹

N.M.R. spectrum (D₂ O, δ) ppm: 8.05 (1H, s), 5.76 (1H, d, J=5 Hz), 5.16(1H, d, J=5 Hz), 4.14 (2H, AB_(q), J=13 Hz), 4.10 (3H, s), 4.02 (3H, s),3.52 (2H, AB_(q), J=17 Hz), 3.45 (3H, s), 3.24 (3H, s).

REFERENCE 4

The following compounds were obtained according to a similar manner tothat of Reference 3.

(1)7-[2-Methoxyimino-2-(2-methyl-1,3-thiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (anti isomer).

I.R. spectrum (Nujol) 1790, 1720, 1680 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.53 (1H, d, J=8 Hz), 8.27 (1H, s),5.83 (1H, dd, J=5.5, 8 Hz), 5.15 (1H, d, J=5.5 Hz), 4.30 (2H, AB_(q),J=14 Hz), 4.00 (3H, s), 3.93 (3H, s), 3.70 (2H, AB_(q), J=16 Hz), 2.65(3H, s).

(2)7-[2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (anti isomer).

I.R. spectrum (Nujol) 3400, 1775, 1670 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.44 (1H, d, J=8 Hz), 7.71 (1H, s),6.40 (2H, broad s), 5.77 (1H, dd, J=5, 8 Hz), 5.13 (1H, d, J=5 Hz), 4.31(2H, broad s), 4.00 (3H, s), 3.95 (3H, s), 3.70 (2H, broad s).

(3)7-[2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-cephalosporanicacid (anti isomer).

I.R. spectrum (Nujol) 3400-3100, 1780, 1730, 1675 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.43 (1H, d, J=8 Hz), 9.16 (2H, broads), 7.73 (1H, s), 5.82 (1H, dd, J=5, 8 Hz), 5.18 (1H, d, J=5 Hz), 4.90(2H, AB_(q), J=13 Hz), 4.03 (3H, s), 3.60 (2H, broad s), 2.07 (3H, s).

(4)7-[2-Methoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (anti isomer), mp 152° C. (dec.).

I.R. spectrum (Nujol) 3300-3100, 1775, 1720, 1670, 1630 cm⁻¹

N.M.R. spectrum (d6-DMSO, δ) ppm: 12.63 (1H, broad s), 9.66 (1H, s),9.57 (1H, d, J=8 Hz), 8.50 (1H, s), 8.07 (1H, s), 5.75 (1H, dd, J=5, 8Hz), 5.15 (1H, d, J=5 Hz), 4.27 (2H, ABq, J=13 Hz), 4.00 (3H, s), 3.70(2H, broad s).

(5)7-[2-Methoxyimino-2-(3-hydroxyphenyl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (anti isomer).

I.R. spectrum (Nujol) 3350, 1780, 1726, 1680 cm⁻¹

    ______________________________________                                        N.M.R.          spectrum (d.sub.6 -DMSO, δ)                             ppm             9.24 (1H, d, J=8Hz)                                                         7.36-7.10                                                                                  (4H, m)                                                          7.00-6.74                                                                     5.70 (1H, dd, J=5,8Hz)                                                        5.13 (1H, d, J=5Hz)                                                           4.34 (2H, AB.sub.q, J=13Hz)                                                   3.95 (6H, s)                                                                  3.72 (2H, AB.sub.q, J=17Hz)                                     ______________________________________                                    

PREPARATION OF THE STARTING COMPOUNDS TO BE USED FOR THE AFOREMENTIONEDEXAMPLES AND REFERENCES PREPARATION 1

A mixture of 3-chloro-4-hydroxyacetophenone (11.9 g.), benzyl chloride(9.35 g.), potassium carbonate (14.5 g.) and dimethylformamide (60 ml.)was stirred for 1 hour at 100° C. The reaction mixture was poured intowater (150 ml.) and extracted with ethyl acetate. The extract was washedwith a sodium chloride aqueous solution and dried over magnesiumsulfate. After distilling off the solvent, the residue (18 g.) wasrecrystallized from ethanol (160 ml.) to give3-chloro-4-benzyloxyacetophenone (13.2 g.), mp 110° to 112° C.

PREPARATION 2

(1) Selenium dioxide powder (12.6 g.) was added over 10 minutes to asolution of 3-chloro-4-benzyloxyacetophenone (19.7 g.) in dry pyridine(100 ml.) with stirring at 100° C., and the mixture was stirred for 3hours at the same temperature. Precipitating selenium was filtered offand the filtrate was concentrated. The residue was dissolved in water(150 ml.) and the solution was washed with ether. The aqueous solutionwas acidified under cooling with conc. hydrochloric acid and extractedwith ether. The extract was washed with a sodium chloride aqueoussolution, dried over magnesium sulfate and concentrated to give2-(3-chloro-4-benzyloxyphenyl)glyoxylic acid (15.9 g.), mp 134° to 135°C.

(2) The following compounds were obtained according to a similar mannerto that of Preparation 2-1).

(1) 2-(3-Nitro-4-benzyloxyphenyl)glyoxylic acid, mp 161° to 164° C.

(2) 2-(3-Chloro-4-methoxyphenyl)glyoxylic acid, mp 81° to 82° C.

I.R. spectrum (Nujol) 2500-2600, 1715, 1670, 1600 cm⁻¹

(3) 2-(3-Mesylaminophenyl)glyoxylic acid, mp 66° to 68° C.

I.R. spectrum (Nujol) 3560, 3250, 1720, 1670 cm⁻¹

PREPARATION 3

(1) A mixture of 2-(3-nitro-4-benzyloxyphenyl)glyoxylic acid (30 g.),conc. hydrochloric acid (90 ml.) and acetic acid (120 ml.) was stirredfor 3 hours at 100° C. To the reaction mixture was added under coolingice-water (600 ml.) and the mixture was extracted with ethyl acetate.The extract was washed with ice-water, dried over magnesium sulfate andconcentrated to dryness under reduced pressure. The residue wasrecrystallized from a mixture of benzene: ether: petroleum ether(2:1:4). The crystals were collected by filtration, washed with benzeneand dried under reduced pressure to give2-(3-nitro-4-hydroxyphenyl)glyoxylic acid (19.0 g.), mp 139° to 140.5°C.

(2) The following compound was obtained according to a similar manner tothat of Preparation 3-1).

(1) 2-(3-Chloro-4-hydroxyphenyl)glyoxylic acid, mp 114° to 116° C.

PREPARATION 4

2-(3-Hydroxyphenyl)glyoxylic acid (3.32 g.) and 1N-methanol solution ofhydroxylamine (45 ml.) were refluxed with stirring for 25 minutes. Thereaction mixture was concentrated under reduced pressure. The residuewas dissolved in 1N-aqueous solution of sodium hydroxide (70 ml.). Anaqueous solution was washed with ether, acidified with dil. hydrochloricacid and then extracted with ethyl acetate. The extract was washed,dried and treated with an activated charcoal. The solvent was distilledoff to give 2-hydroxyimino-2-(3-hydroxyphenyl)acetic acid (a mixture ofsyn and anti isomers) (2.9 g.).

I.R. spectrum (Nujol) 3200, 1700 cm⁻¹

PREPARATION 5

(1)(a) Phenolphthalein indicator (3 drops) was added to a solution ofO-methylhydroxylamine hydrochloride (5.5 g.) in dry methanol (60 ml.).To the solution was dropwise added with stirring at ambient temperature1N methanol solution of sodium methoxide (65 ml.) until the color of thesolution was changed to purplish red. O-Methylhydroxylaminehydrochloride was added thereto by small portions until the solution waschanged to colorless solution. The mixture was stirred for 30 minutes atambient temperature. After precipitating sodium chloride was filteredoff, 2-(3-hydroxyphenyl)glyoxylic acid (9.85 g.) was added to thefiltrate and the mixture was refluxed for 30 minutes. After methanol wasdistilled off at low temperature, a saturated sodium chloride aqueoussolution was added to the residue. The mixture was adjusted to pH 1 with10% hydrochloric acid and extracted with ether (300 ml.). The extractwas dried over magnesium sulfate. Ether was distilled off at lowtemperature to give 2-methoxyimino-2-(3-hydroxyphenyl)acetic acid (amixture of syn and anti isomers).

(b) This material was dissolved in ether (60 ml.) and a solution ofdiazomethane in ether was gradually added thereto under ice-coolinguntil the color of the mixture was changed to yellow. Acetic acid wasimmediately added thereto and the mixture was washed with a sodiumbicarbonate aqueous solution and a saturated sodium chloride aqueoussolution and dried over magnesium sulfate. Ether was distilled off togive oily residue (10.8 g.). The oily residue was subjected to columnchromatography on silica gel (165 g.) using a mixture of benzene andethyl acetate (9:1) as developing solvent. Firstly the eluate containingsyn isomer was eluted and the eluate was collected and concentrated togive oily methyl 2-methoxyimino-2-(3-hydroxyphenyl)acetate (syn isomer)(7.9 g.). The oil was allowed to stand to give crystals, mp 39.5° to40.5° C.

I.R. spectrum (Nujol) 3450, 1730 cm⁻¹

N.M.R. spectrum (CDCl₃, δ) ppm: 6.7-7.42 (4H, m), 3.98 (3H, s), 3.92(3H, s).

After the eluate containing syn isomer was eluted, then the eluatecontaining anti isomer was eluted. The eluate was collected andconcentrated to give methyl 2-methoxyimino-2-(3-hydroxyphenyl)acetate(anti isomer) (1.5 g.). This material was recrystallized from a mixtureof benzene and petroleum ether to give crystals, mp 96° to 98° C.

I.R. spectrum (Nujol) 3350, 1715 cm⁻¹

N.M.R. spectrum (CDCl₃, δ) ppm: 7.12-7.40 (1H, m), 6.96-7.02 (3H, m),3.99 (3H, s), 3.84 (3H, s).

(c) A 2N aqueous solution of sodium hydroxide (40 ml.) was added withstirring at ambient temperature to a suspension of methyl2-methoxyimino-2-(3-hydroxyphenyl)acetate (syn isomer) (7.55 g.) inwater (70 ml.) and the mixture was stirred for 1 hour at ambienttemperature. The reaction mixture was adjusted to pH 6.5 with 10%hydrochloric acid, subjected to salting-out and washed with ether (60ml.). The aqueous layer was adjusted to pH 1 with conc. hydrochloricacid and extracted once with 100 ml. of and twice with 60 ml. of ether.The extract was washed twice with a saturated sodium chloride aqueoussolution (60 ml.) and dried over magnesium sulfate. Ether was distilledoff to give oil. Benzene was added thereto and removed (twice) to givecrystals of 2-methoxyimino-2-(3-hydroxyphenyl)acetic acid (syn isomer)(6.44 g.), mp 98° to 101° C. (dec.).

I.R. spectrum (Nujol) 3370, 1720 cm⁻¹

An aqueous solution of 2N sodium hydroxide (8 ml.) was added withstirring at ambient temperature to a solution of methyl2-methoxyimino-2-(3-hydroxyphenyl)acetate (anti isomer) (1.56 g.) inmethanol (30 ml.). After stirring for 3 hours at the same temperature,methanol was distilled off. To the residue was added water and themixture was washed with ether. The aqueous layer was adjusted to pH 1with 10% hydrochloric acid, subjected to salting-out and extracted withether. The extract was washed with a sodium chloride aqueous solutionand dried over magnesium sulfate. Ether was distilled off to givecrystals of 2-methoxyimino-2-(3-hydroxyphenyl)acetic acid (anti isomer)(1.07 g.). The crystals were recrystallized from a mixture of petroleumether and ether to give crystals (0.7 g.), mp 99° to 101° C. (dec.).

I.R. spectrum (Nujol) 3350, 1690 cm⁻¹

(2)(a) Phenolphthalein indicator (3 drops) was added to a solution ofO-methylhydroxylamine hydrochloride (3.7 g.) in dry methanol (45 ml.).To the solution was dropwise added with stirring at ambient temperature1N methanol solution of sodium methoxide (39 ml.) until the color of thesolution was changed to purplish red. O-Methylhydroxylaminehydrochloride was added thereto by small portions until the solution waschanged to colorless solution. The mixture was stirred for 30 minutes atambient temperature. After precipitating sodium chloride was filteredoff, 2-(4-hydroxyphenyl)glyoxylic acid (6.56 g.) was added to thefiltrate and the mixture was stirred for 1 hour at ambient temperature.After methanol was distilled off at low temperature, a saturated sodiumchloride aqueous solution was added to the residue. The mixture wasadjusted to pH 1 with 10% hydrochloric acid, subjected to salting-outand extracted with ether. The extract was dried over magnesium sulfate.Ether was distilled off at low temperature to give2-methoxyimino-2-(4-hydroxyphenyl)-acetic acid (syn isomer).

(b) This material was dissolved in ether (50 ml.) and a solution ofdiazomethane in ether was gradually added thereto under ice-coolinguntil the color of the mixture was changed to yellow. Acetic acid wasimmediately added thereto and the mixture was washed with a sodiumbicarbonate aqueous solution and a saturated sodium chloride aqueoussolution and dried over magnesium sulfate. Ether was distilled off togive oily residue (8 g.). The oily residue was subjected to columnchromatography on silica gel using a mixture of benzene and ethylacetate (9:1) as developing solvent to give methyl2-methoxyimino-2-(4-hydroxyphenyl)acetate (syn isomer) (6.39 g.).

I.R. spectrum (Nujol) 3350, 1720 cm⁻¹

N.M.R. spectrum (CDCl₃, δ) ppm: 7.40 (2H, d, J=8 Hz), 6.80 (2H, d, J=8Hz), 3.96 (3H, s), 3.92 (3H, s).

(c) A 2N aqueous solution of sodium hydroxide (11 ml.) was added withstirring at ambient temperature to a solution of methyl2-methoxyimino-2-(4-hydroxyphenyl)acetate (syn isomer) (2.1 g.) inmethanol (30 ml.) and the mixture was stirred for 18 hours at ambienttemperature. The reaction mixture was adjusted to pH 7 with 10%hydrochloric acid and methanol was removed. To the residue was addedwater and the mixture was washed with ether. The aqueous layer wasadjusted to pH 1 with 10% hydrochloric acid, subjected to salting-outand extracted with ethyl acetate. The extract was washed with asaturated sodium chloride aqueous solution and dried over magnesiumsulfate. Ethyl acetate was distilled off to give crystals of2-methoxyimino-2-(4-hydroxyphenyl)acetic acid (syn isomer) (1.5 g.).

I.R. spectrum (Nujol) 3150, 1700 cm⁻¹

(3)(a) Phenolphthalein indicator (2 drops) was added to a solution ofO-methylhydroxylamine hydrochloride (2.74 g.) in dry methanol (30 ml.).To the solution was dropwise added with stirring at ambient temperature1N methanol solution of sodium methoxide until the color of the solutionwas changed to purplish red. O-Methylhydroxylamine hydrochloride wasadded thereto by small portions until the solution was changed tocolorless solution. The mixture was stirred for 1 hour at ambienttemperature. After precipitating sodium chloride was filtered off,2-(3-nitro-4-hydroxyphenyl)glyoxylic acid (6.75 g.) was added to thefiltrate and the mixture was stirred for 1 hour at ambient temperature.After methanol was distilled off at 35° C., a saturated sodium chlorideaqueous solution was added to the residue. The mixture was adjusted topH 1 with 10% hydrochloric acid and extracted with ether. The extractwas dried over magnesium sulfate. Ether was distilled off at 35° C.under reduced pressure to give yellow crystals of2-methoxyimino-2-(3-nitro-4-hydroxyphenyl)acetic acid (a mixture of synand anti isomers) (7 g.).

(b) This material was dissolved in a mixture of tetrahydrofuran (15 ml.)and ether (100 ml.) and a solution of diazomethane in ether wasgradually added thereto at ambient temperature until the color of themixture was changed to yellow. Acetic acid was immediately added theretoand the mixture was concentrated to dryness at 35° C. under reducedpressure. The residue was dissolved in a mixed solvent of ethyl acetateand benzene (1:9) and subjected to column chromatography on silica gelusing the same mixed solvent as developing solvent. The eluatecontaining syn isomer was collected and concentrated to give methyl2-methoxyimino-2-(3-nitro-4-hydroxyphenyl)acetate (syn isomer) (3.7 g.),mp 93° to 95° C.

I.R. spectrum (Nujol) 3300, 1745, 1630, 1535, 1350 cm⁻¹

N.M.R. spectrum (CDCl₃, δ) ppm: 10.87 (1H, s), 8.22 (1H, d, J=2 Hz),7.86 (1H, dd, J=2, 8 Hz), 7.20 (1H, d, J=8 Hz), 4.03 (3H, s), 3.95 (3H,s).

(c) A 2N aqueous solution of sodium hydroxide (14 ml.) was added withstirring at ambient temperature to a solution of methyl2-methoxyimino-2-(3-nitro-4-hydroxyphenyl)acetate (syn isomer) (3.5 g.)in methanol (70 ml.) and the mixture was stirred for 60 hours ambienttemperature. The reaction mixture was concentrated to dryness at 40° C.under reduced pressure and the residue was dissolved in water. Thesolution was washed with ethyl acetate, adjusted to pH 1 with 10%hydrochloric acid under ice-cooling and extracted with ethyl acetate.The extract was back-extracted with a saturated sodium bicarbonateaqueous solution. The aqueous extract was adjusted to pH 1 with conc.hydrochloric acid under ice-cooling and extracted with ethyl acetate.The extract was washed with ice-water and dried over magnesium sulfate.The solvent was concentrated to dryness at 40° C. under reduced pressureto give yellow crystals of2-methoxyimino-2-(3-nitro-4-hydroxyphenyl)acetic acid (syn isomer) (3.2g.), mp 142° to 143° C. (dec.).

I.R. spectrum (Nujol) 3300, 2500-2600, 1710, 1630, 1600, 1535, 1375 cm⁻¹

N.M.R. spectrum (CDCl₃, δ) ppm: 10.67 (2H, s), 8.33 (1H, d, J=2 Hz),7.95 (1H, dd, J=2, 8 Hz), 7.22 (1H, d, J=8 Hz), 4.13 (3H, s).

(4) (a) 2-(3-Chloro-4-hydroxyphenyl)glyoxylic acid (6.45 g.) andO-methylhydroxylamine hydrochloride (2.74 g.) were reacted according toa similar manner to that of Preparation 5-3) (a) to give oil of2-methoxyimino-2-(3-chloro-4-hydroxyphenyl)-acetic acid (a mixture ofsyn and anti isomers) (7 g.).

(b) 2-Methoxyimino-2-(3-chloro-4-hydroxyphenyl)acetic acid (a mixture ofsyn and anti isomers) (7 g.) and diazomethane (1.5 g.) were reacted andthe product was purified by column chromatography according to a similarmanner to that of Preparation 5-3) (b) to give crystals of methyl2-methoxyimino-2-(3-chloro-4-hydroxyphenyl)acetate (syn isomer) (3.0g.).

I.R. spectrum (Film) 3450, 1735, 1605, 1600 cm⁻¹

N.M.R. spectrum (CDCl₃, δ) ppm: 7.55 (1H, d, J=2 Hz), 7.37 (1H, dd, J=2,8 Hz), 6.95 (1H, d, J=8 Hz), 6.12 (1H, s), 3.97 (3H, s), 3.91 (3H, s).

(c) Methyl 2-methoxyimino-2-(3-chloro-4-hydroxyphenyl)-acetate (synisomer) (2.6 g.) and a 2N aqueous solution of sodium hydroxide (10.6ml.) were treated according to a similar manner to that of Preparation5-3) (c) to give 2-methoxyimino-2-(3-chloro-4-hydroxyphenyl)acetic acid(syn isomer) (2.4 g.), mp 147° to 150° C. (dec.).

I.R. spectrum (Nujol) 3500, 2500-2600, 1745, 1610, 1600 cm⁻¹

N.M.R. spectrum (CDCl₃, δ) ppm: 8.40 (2H, broad s), 7.65 (1H, d, J=2Hz), 7.40 (1H, dd, J=2, 8 Hz), 7.00 (1H, d, J=8 Hz), 4.07 (3H, s).

(5) 2-(3-Hydroxyphenyl)glyoxylic acid (2.0 g.) and O-allylhydroxylaminehydrochloride (1.7 g.) were reacted according to a similar manner tothat of Preparation 5-2) (a) to give oil of2-allyloxyimino-2-(3-hydroxyphenyl)acetic acid (syn isomer) (2.7 g.).

I.R. spectrum (Film) 3350, 2550-2600, 1720, 1645, 1600 cm⁻¹

(6) 2-(3-Chloro-4-hydroxyphenyl)glyoxylic acid (2 g.) andO-allylhydroxylamine hydrochloride (1.1 g.) were reacted according to asimilar manner to that of Preparation 5-2) (a) to give oil of2-allyloxyimino-2-(3-chloro-4-hydroxyphenyl)acetic acid (syn isomer)(2.5 g.).

I.R. spectrum (Film) 3450, 2600, 1730, 1700, 1650, 1610, 1600 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.5-10.5 (2H, broad s), 7.52 (1H, d,J=2 Hz), 7.42 (1H, dd, J=2, 8 Hz), 7.12 (1H, d, J=8 Hz), 6.0 (1H, m),5.40 (2H, t, J=8 Hz), 4.70 (2H, d, J=5 Hz).

(7) A mixture of 2-(3-chloro-4-hydroxyphenyl)glyoxylic acid (2.0 g.),O-t-butoxycarbonylmethylhydroxylamine (1.62 g.) and methanol (20 ml.)was adjusted to pH 5 to 6 by adding an 1N methanol solution of sodiummethoxide and stirred for 3 hours at ambient temperature. The reactionmixture was concentrated to dryness under reduced pressure and theresidue was dissolved in an 1N aqueous solution of sodium hydroxide toadjust to pH 7.0. The aqueous solution was washed with ether, adjustedto pH 2.0 with 10% hydrochloric acid under ice-cooling and extractedwith ether. The extract was washed with water and dried over magnesiumsulfate. The solution was concentrated to dryness under reduced pressureto give crystals of2-t-butoxycarbonylmethoxyimino-2-(3-chloro-4-hydroxyphenyl)acetic acid(syn isomer) (2.6 g.), mp 116° to 118° C. (dec.).

I.R. spectrum (Nujol) 3250, 2600, 1735, 1690, 1670, 1610, 1590 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 11.00 (2H, broad s), 7.50 (1H, d, J=2Hz), 7.40 (1H, dd, J=2, 8 Hz), 7.08 (1H, d, J=8 Hz), 4.68 (2H, s), 1.45(9H, s).

(8) (a) Potassium carbonate (49.7 g.) and dimethyl sulfate (45.4 g.)were added to a solution of 2-hydroxyimino-2-(3-hydroxyphenyl)aceticacid (a mixture of syn and anti isomers) (18.1 g.) in dry acetone (250ml.) and the mixture was refluxed with stirring for 8.5 hours. Afteracetone was distilled off, the residue was dissolved in water andextracted with ethyl acetate. The extract was washed with a sodiumchloride aqueous solution and dried over magnesium sulfate. The solventwas distilled off to give oil (24 g.). The oil was subjected to columnchromatography on silica gel using benzene as developing solvent.Firstly the eluate containing syn isomer was eluted and the eluate wascollected and concentrated to give oil of methyl2-methoxyimino-2-(3-methoxyphenyl)acetate (syn isomer) (9.2 g.).

I.R. spectrum (Film) 1738 cm⁻¹

N.M.R. spectrum (CDCl₃, δ) ppm: 7.47-6.77 (4H, m), 4.00 (3H, s), 3.92(3H, s), 3.82 (3H, s).

After the eluate containing syn isomer was eluted, then the eluatecontaining anti isomer was eluted. The eluate was collected andconcentrated to give methyl 2-methoxyimino-2-(3-methoxyphenyl)acetate(anti isomer) (3.9 g.), mp 66° to 68° C. This substance wasrecrystallized from petroleum ether to give prisms, mp 65° to 65.5° C.

I.R. spectrum (Nujol) 1720 cm⁻¹

N.M.R. spectrum (CDCl₃, δ) ppm: 7.14-7.44 (1H, m), 6.80-7.04 (3H, m),4.02 (3H, s), 3.84 (3H, s), 3.76 (3H, s).

(b) Methyl 2-methoxyimino-2-(3-methoxyphenyl)acetate (syn isomer) (1.6g.) and a 2N aqueous solution of sodium hydroxide (4 ml.) were treatedaccording to a similar manner to that of Preparation 5-3) (c) to giveoil of 2-methoxyimino-2-(3-methoxyphenyl)acetic acid (syn isomer) (1.23g.).

I.R. spectrum (Film) 1735 cm⁻¹

Methyl 2-methoxyimino-2-(3-methoxyphenyl)acetate (anti isomer) (1.6 g.)and a 2N aqueous solution of sodium hydroxide (4 ml.) were treatedaccording to a similar manner to that of Preparation 5-3) (c) to givecolorless prisms of 2-methoxyimino-2-(3-methoxyphenyl)acetic acid (antiisomer) (1.3 g.), mp 97° to 98° C.

I.R. spectrum (Nujol) 1695 cm⁻¹

(9) (a) A solution of diazomethane in ether was added at ambienttemperature to a solution of2-methoxyimino-2-(3-chloro-4-hydroxyphenyl)acetic acid (syn isomer) (7g.) in dry ether (50 ml.) until the color of the mixture was changed toyellow. Acetic acid was immediately added thereto and the reactionmixture was concentrated to dryness at 35° C. under reduced pressure.The residue was subjected to column chromatography on silica gel (120g.) using a mixture of benzene and ethyl acetate (9:1) as a developingsolvent. The first eluate was collected and concentrated at 40° C. underreduced pressure to give oil of methyl2-methoxyimino-2-(3-chloro-4-methoxyphenyl)acetate (syn isomer) (3.1g.).

I.R. spectrum (Film) 2850, 1735, 1610, 1600, 1250 cm⁻¹

N.M.R. spectrum (CDCl₃, δ) ppm: 7.57 (1H, d, J=2 Hz), 7.37 (1H, dd, J=2,8 Hz), 6.87 (1H, d, J=8 Hz), 3.97 (3H, s), 3.91 (3H, s), 3.88 (3H, s).

(b) Methyl 2-methoxyimino-2-(3-chloro-4-methoxyphenyl)acetate (synisomer) (2.7 g.) and a 2N aqueous solution of sodium hydroxide (10.6ml.) were treated according to a similar manner to that of Preparation5-3) (c) to give crystals of2-methoxyimino-2-(3-chloro-4-methoxyphenyl)acetic acid (syn isomer) (2.6g.), mp 133° to 135° C. (dec.).

I.R. spectrum (Nujol) 2500-2600, 1745, 1610, 1600 cm⁻¹

N.M.R. spectrum (CDCl₃, δ) ppm: 9.95 (1H, broad s), 7.72 (1H, d, J=2Hz), 7.50 (1H, dd, J=2, 8 Hz), 6.92 (1H, d, J=8 Hz), 4.08 (3H, s), 3.95(3H, s).

(10) (a) A solution of 2-bromopropionyl bromide (25 g.) in drychloroform (50 ml.) was dropwise added with stirring and ice-cooling toa solution of N,N-dimethylaniline (24 g.) in t-butanol (11 g.) and themixture was refluxed for 2 hours. After cooling, the reaction mixturewas poured into 6N sulfuric acid (150 ml.) and extracted with ether. Theextract was in turn washed with 6N sulfuric acid, water, a 10% potassiumcarbonate aqueous solution and water and dried over magnesium sulfate.The solvent was distilled off to give oil of t-butyl 2-bromopropionate(21 g.).

(b) This oil (21 g.) was added with stirring at ambient temperature to amixture of N-hydroxyphthalimide (16.3 g.), triethylamine (24 g.),dimethylformamide (20 ml.) and dimethylsulfoxide (20 ml.) and theresulting mixture was stirred for 4 hours at ambient temperature. Thereaction mixture was poured into water (800 ml.) and precipitatingmaterials were collected by filtration, washed with water and dried togive t-butyl 2-phthalimidoxypropionate (22.7 g.). (c) This compound(22.7 g.) was dissolved in methylene chloride (200 ml.). A solution of10% hydrazine hydrate (9 ml.) in methanol (20 ml.) was added thereto andthe mixture was stirred for 2 hours at ambient temperature.Precipitating materials were dissolved by adding 5N aqueous solution ofammonia and the aqueous layer was extracted with methylene chloride. Twomethylene chloride layers were combined and dried over magnesiumsulfate. The solvent was distilled off under reduced pressure to giveoil of 0-(1-t-butoxycarbonylethyl)hydroxylamine (13.5 g.).

I.R. spectrum (Film) 3350, 3250, 1745 cm⁻¹

(d) 2-(3-Chloro-4-hydroxyphenyl)glyoxylic acid (2.0 g.) and0-(1-t-butoxycarbonylethyl)hydroxylamine (3.2 g.) were reacted accordingto a similar manner to that of Preparation 5-7) to give2-(1-t-butoxycarbonylethoxyimino)-2-(3-chloro-4-hydroxyphenyl)aceticacid (syn isomer) (3.3 g.), mp 148° to 151° C.

I.R. spectrum (Nujol) 3450, 2500-2600, 1725, 1690, 1620, 1600 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 7.46 (1H, d, J=2 Hz), 7.33 (1H, dd,J=2, 8 Hz), 7.07 (1H, d, J=8 Hz), 4.67 (1H, q, J=6 Hz), 1.50 (12H, s).

(11) Phenolphthalein indicator (3 drops) was added to a solution ofO-methylhydroxylamine hydrochloride (8.8 g.) in dry methanol (60 ml.).To the solution was dropwise added with stirring at ambient temperature1N methanol solution of sodium methoxide (105 ml.) until the color ofthe solution was changed to pale pink. O-Methylhydroxylaminehydrochloride was added thereto by small portions until the solution waschanged to colorless solution. The pH value of the solution was 8.0 to8.5. The mixture was stirred for 30 minutes at ambient temperature.After precipitating sodium chloride was filtered off,2-(3-hydroxyphenyl)glyoxylic acid (16.6 g.) was added to the filtrateand the mixture was stirred for 1 hours at ambient temperature. Aftermethanol was distilled off at low temperature, water was added to theresidue. The mixture was adjusted to pH 7 with an aqueous solution ofsodium bicarbonate, washed with ether, adjusted to pH 1 with 10%hydrochloric acid, subjected to salting-out and extracted with ether.The extract was washed with a saturated sodium chloride aqueous solutionand dried over magnesium sulfate. Ether was distilled off and theoperation that benzene was added to the residue and distilled off wasrepeated twice to give crystals of2-methoxyimino-2-(3-hydroxyphenyl)acetic acid (syn isomer) (14.8 g.).This compound was identified with the compound obtained in Preparation5- 1) (c) by I.R. spectrum.

(12) A solution of 2-(3-methoxyphenyl)glyoxylic acid (1.8 g.) in anaqueous solution of sodium bicarbonate was adjusted to pH 7.0. On theother hand, a solution of O-ethylhydroxylamine hydrochloride (1.4 g.) inwater (20 ml.) was adjusted to pH 7.0 with sodium bicarbonate. Twosolutions were combined together, adjusted to pH 5.5 with 10%hydrochloric acid and stirred overnight at ambient temperature. Thereaction mixture was adjusted to pH 7.5 with sodium bicarbonate andwashed with ethyl acetate. The aqueous layer was adjusted to pH 1.0 withconc. hydrochloric acid under ice-cooling and extracted with ethylacetate. The extract was washed with ice-water and dried over magnesiumsulfate. The solvent was distilled off under reduced pressure to giveoil of 2-ethoxyimino-2-(3-methoxyphenyl)acetic acid (syn isomer) (2.2g.).

I.R. spectrum (Film) 2600, 1735, 1700, 1610, 1600 cm⁻¹

(13) The following compounds were obtained according to similar mannersto those of Preparation (5-5) to (5-7) and (5-10) to (5-12).

(1) 2-Ethoxyimino-2-(3-chloro-4-hydroxyphenyl)acetic acid (syn isomer),oil.

I.R. spectrum (Film) 3450, 2250-2600, 1700-1720, 1610, 1600 cm⁻¹

(2) 2-Ethoxyimino-2-(3-hydroxyphenyl)acetic acid (syn isomer) oil.

I.R. spectrum (Film) 3400, 2600, 1700-1730, 1605, 1600 cm⁻¹

(3) 2-(3-Hydroxy-4-bromobenzyloxyimino)-2-(4-hydroxyphenyl)acetic acid(syn isomer), colorless powder.

I.R. spectrum (Nujol) 3500, 3200, 1700 cm⁻¹

N.M.R. spectrum (d₆ -acetone, δ) ppm: 6.68-8.05 (7H, m), 5.15 (2H, s).

(4) 2-(2-Thienylmethoxyimino)-2-(4-hydroxyphenyl)acetic acid (synisomer), powder.

I.R. spectrum (Nujol) 1705 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 6.7-7.7 (7H, m), 5.28 (2H, s).

(5) 2-Allyloxyimino-2-(3-methoxyphenyl)acetic acid (syn isomer), oil.

I.R. spectrum (Film) 3050-3100, 2600, 1730, 1645, 1610, 1600 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 7.00-7.50 (4H, m), 5.80-6.30 (1H, m),5.33 (2H, t, J=9 Hz), 4.70 (2H, d, J=5 Hz), 3.82 (3H, s).

(6) 2-Allyloxyimino-2-(3-chloro-4-methoxyphenyl)acetic acid (synisomer), pale yellow oil.

I.R. spectrum (Film) 3100, 2600, 1710-1730, 1645, 1610, 1600 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 7.63 (1H, d, J=2 Hz), 7.50 (1H, dd,J=2,8 Hz), 7.23 (1H, d, J=8 Hz), 5.9-6.3 (1H, m), 5.33 (2H, t, J=9 Hz),4.73 (2H, d, J=5 Hz), 3.91 (3H, s).

(7) 2-Phenylthiomethoxyimino-2-(3-hydroxyphenyl)acetic acid (synisomer), oil.

I.R. spectrum (Film) 3300, 1730 cm⁻¹

N.M.R. spectrum (CDCl₃, δ) ppm: 6.8-7.7 (9H, m), 5.54 (2H, s).

(8) 2-Methoxyimino-2-(3-mesylaminophenyl)acetic acid (syn isomer), mp128° C. (dec.).

I.R. spectrum (Nujol) 3300, 1740 cm⁻¹

(9) 2-(3-Phenylallyloxyimino)-2-(3-hydroxyphenyl)acetic acid (synisomer), mp 115° to 116° C.

I.R. spectrum (Nujol) 3400, 1725 cm⁻¹

(10) 2-Methoxyimino-2-(4-dimethylamino-phenyl)acetic acid (syn isomer),mp 88° to 89° C. (dec.).

I.R. spectrum (Nujol) 2700-2100, 1720, 1660, 1612, 1590 cm⁻¹

(14) Acetyl chloride (4.1 g.) was added with stirring and ice-cooling toa solution of 2-methoxyimino-2-(3-hydroxyphenyl)acetic acid (syn isomer)(5 g.) in pyridine (20 ml.) and the mixture was stirred for 50 minutesat ambient temperature. The reaction mixture was poured into ice-water,adjusted to pH 2.1 and extracted three times with ether. The extract waswashed with a saturated sodium chloride aqueous solution and dried overmagnesium sulfate. The solvent was thoroughly removed under reducedpressure to give 2-methoxyimino-2-(3-acetoxyphenyl)acetic acid (synisomer) (6.1 g.).

I.R. spectrum (Film) 3500, 2950, 1760, 1735, 1605, 1575, 1485, 1440,1425, 1370 cm⁻¹

N.M.R. spectrum (CDCl₃, δ) ppm: 7.94 (1H, s), 7.6-7.0 (4H, m), 4.05 (3H,s), 2.30 (3H, s).

(15) Trichloroacetyl isocyanate (70 ml) was dropwise added over 6minutes at ambient temperature to a solution of2-methoxyimino-2-(3-hydroxyphenyl)acetic acid (syn isomer) (40 g) in drydioxane (200 ml), and the resulting mixture was stirred for 5 hours atambient temperature. Dioxane was distilled off and to the residue wereadded ethyl acetate (200 ml) and by small portions water (200 ml) underice-cooling. The mixture containing trichloroacetylcarbamoyl2-methoxyimino-2-(3-trichloroacetylcarbamoyloxyphenyl)acetate wasstirred for 5 hours at ambient temperature keeping the pH value of themixture at 6.0 to 6.4 by adding an aqueous solution of sodiumbicarbonate. The resulting mixture was washed twice with ethyl acetate.The aqueous layer was adjusted to pH2 with a 10% hydrochloric acid andextracted three times with ethyl acetate. The combined ethyl acetateextracts were washed twice with an aqueous solution of sodium chlorideand dried over magnesium sulfate. The solvent was distilled off andprecipitating crystals were collected by filtration to give colorlesscrystals of 2-methoxyimino-2-(3-carbamoyloxyphenyl)acetic acid (synisomer) (15 g), mp 163° C. (dec.). The same compound (5.4 g) wasobtained from the mother liquor.

I.R. spectrum (Nujol) 3480, 3360, 1730, 1660 cm⁻¹

N.M.R. spectrum (d6-DMSO, δ) ppm: 3.97 (3H, s), 7.16 (2H, broad s),7.1-7.7 (4H, m), 9.7 (1H, broad s).

PREPARATION 6

(1) A solution of sodium nitrite (12.4 g.) in water (150 ml.) wasdropwise added with stirring at 5° to 7° C. to a solution of ethyl4-bromoacetoacetate (30 g.) in acetic acid (200 ml.) and the mixture wasstirred for 2 hours at 10° C. Water (200 ml.) was added to the reactionmixture and the resultant mixture was extracted with ether (500 ml.).The extract was washed twice with water (200 ml.) and with a sodiumchloride aqueous solution (200 ml.) and dried over magnesium sulfate.The solvent was distilled off under reduced pressure to give yellowishbrown crystals of ethyl 2-hydroxyimino-4-bromoacetoacetate (a mixture ofsyn and anti isomers) (32.6 g.).

I.R. spectrum (Film) 3350, 1740, 1710, 1620 cm⁻¹

N.M.R. spectrum (CDCl₃, δ) ppm: 8.75 (2H, broad s), 4.35 (8H, m), 1.35(6H, m).

(2) Pulverized potassium carbonate (160 g.) was added to a solution ofethyl 2-hydroxyiminoacetoacetate (a mixture of syn and anti isomers)(152 g.) in acetone (500 ml.). Dimethyl sulfate (130 g.) was dropwiseadded thereto with stirring over 1 hour at 45° to 50° C. and the mixturewas stirred for 2 hours. An insoluble material was filtered off and thefiltrate was concentrated under reduced pressure. The filtered insolublematerial was dissolved in water (500 ml.) and this solution was added tothe residue. The mixture was extracted twice with ethyl acetate (300ml.). The extract was washed twice with water (200 ml.) and with asaturated sodium chloride aqueous solution (200 ml.) and dried overmagnesium sulfate. The solvent was distilled off under reduced pressureand the residue was distilled under reduced pressure to give colorlessoil of ethyl 2-methoxyiminoacetoacetate (a mixture of syn and antiisomers) (145.3 g.), bp 55° to 64° C./0.5 mm Hg.

I.R. spectrum (Film) 1745, 1695, 1600 cm⁻¹

N.M.R. spectrum (CDCl₃, δ) ppm: 4.33 (4H, q, J=8 Hz), 4.08 (3H, s), 3.95(3H, s), 2.40 (3H, s), 1.63 (3H, s), 1.33 (6H, t, J=8 Hz).

(3) Bromine (100 g.) was dropwise added over 40 minutes under reflux toa solution of ethyl 2-methoxyiminoacetoacetate (a mixture of syn andanti isomers) (100 g.) in a mixture of carbon tetrachloride (300 ml.)and acetic acid (300 ml.). The mixture was stirred at 70° to 80° C.until the evolution of hydrogen bromide ceased. The reaction mixture waswashed twice with water (300 ml.), a sodium bicarbonate aqueous solutionand a saturated sodium chloride aqueous solution and dried overmagnesium sulfate. The solution was treated with activated charcoal (2g.) and concentrated under reduced pressure to give ethyl2-methoxyimino-4-bromoacetoacetate (a mixture of syn and anti isomers)(120.8 g.).

I.R. spectrum (Film) 1740, 1705, 1600 cm⁻¹

N.M.R. spectrum (CDCl₃, δ), ppm: 4.17-4.54 (8H, m), 4.15 (3H, s), 4.13(3H, s), 1.33 (6H, t, J=8 Hz).

(4) A mixture of selenium dioxide (11.1 g.), dioxane (250 ml.) and water(5 ml.) was stirred for 15 minutes at 110° to 115° C. to give yellowsolution. Ethyl 2-(2-mesylamino-1,3-thiazol-4-yl)acetate (26.4 g) wasadded thereto with stirring at the same temperature. After stirring for1 hour, the reaction mixture was decanted with heating and cooled toprecipitate yellow crystals. The crystals were collected by filtration,washed with dioxane and ether and dried to give ethyl2-(2-mesylamino-1,3-thiazol-4-yl)glyoxylate (23.5 g.).

I.R. spectrum (Nujol) 3300, 1718, 1682 cm⁻¹

(5) Ethyl 2-(2-mesylamino-1,3-thiazol-4-yl)glyoxylate (13.9 g.) wasadded with stirring at ambient temperature to a solution of sodiumhydroxide (5.0 g.) in water (150 ml.). The mixture was stirred for 1hour at ambient temperature, adjusted to pH 7 with conc. hydrochloricacid and washed with ethyl acetate. The aqueous layer was adjusted to pH0.5 with conc. hydrochloric acid to precipitate yellow crystals. Thecrystals were collected by filtration, washed with water and dried togive 2-(2-mesylamino-1,3-thiazol-4-yl)glyoxylic acid (10.16 g.).

I.R. spectrum (Nujol) 3350, 1725, 1650 cm⁻¹

(6) To a solution of ethyl 2-(2-amino-1,3-thiazol-4-yl)acetate (14 g.)in a mixture of pyridine (40 g.) and methylene chloride (300 ml.) wasgradually added diethyl ether solution of t-pentyl chloroformate (70ml.) containing 0.35 mole of t-pentyl chloroformate over 10 minutes at-20° C. with stirring, and the mixture was stirred for 2 hours at thesame temperature and further stirred for 0.5 hour at 0° C. After thereaction, the reaction mixture was poured into water (200 ml.), and thenthe organic layer was separated. The organic layer was washed with 2Nhydrochloric acid, water, 5% sodium bicarbonate aqueous solution andwater in turn and then dried over magnesium sulfate. The solvent wasdistilled off from the organic layer to give dark brown oil of ethyl2-(2-t-pentyloxycarbonylamino-1,3-thiazol-4-yl)acetate (12 g.).

I.R. spectrum (liquid) 1667, 1660 (CO) cm⁻¹

N.M.R. spectrum (CDCl₃, δ) ppm: 3.75 (2H, s), 6.75 (1H, s).

(7) Ethyl 2-(2-t-pentyloxycarbonylamino-1,3-thiazol-4-yl)acetate (0.3g.) and selenium dioxide (0.11 g.) were treated according to a similarmanner to that of Preparation 6-4) to give brown oil of ethyl2-(2-t-pentyloxycarbonylamino-1,3-thiazol-4-yl)glyoxylate (0.22 g.).

I.R. spectrum (liquid) 1720, 1690 (CO) cm⁻¹

N.M.R. spectrum (CDCl₃, δ) ppm: 8.3 (1H, s).

(8) Ethyl 2-(2-t-pentyloxycarbonylamino-1,3-thiazol-4-yl)glyoxylate (2.8g.) and a solution of sodium hydroxide (0.54 g.) in water (20 ml.) weretreated according to a similar manner to that of Preparation 6-5) togive brown powder of2-(2-t-pentyloxycarbonylamino-1,3-thiazol-4-yl)glyoxylic acid (1.75 g.).

I.R. spectrum (Nujol) 1730, 1680 (CO) cm⁻¹

N.M.R. spectrum (d₆ -dimethylsulfoxide, δ) ppm: 8.4 (1H, s).

(9) A mixture of ethyl2-hydroxyimino-2-(2-amino-1,3-thiazol-4-yl)acetate (a mixture of syn andanti isomers) (0.37 g), ethanol (5 ml), water (5 ml) and sodiumbisulfite (0.72 g) was stirred for 12 hours at 65° to 70° C. Thereaction mixture was concentrated and water (10 ml) was added to theresidue. The resulting mixture was subjected to salting-out andextracted with ethyl acetate. The extract was dried over magnesiumsulfate and concentrated to give yellow crystals of ethyl2-(2-amino-1,3-thiazol-4-yl)glyoxylate (0.18 g), mp 115° to 120° C.

I.R. spectrum (Nujol) 3420, 3250, 3120, 1730, 1665, 1612 cm⁻¹

(10) Sulfuryl chloride (235 ml.) was dropwise added over 20 minutes withstirring and ice-cooling to a solution of ethyl2-methoxyiminoacetoacetate (syn isomer) (500 g.) in acetic acid (500ml.), and the mixture was stirred overnight under cooling with water.Nitrogen gas was introduced to the reaction mixture for 2 hours, and theresulting mixture was poured into water (2.5 l). After extracting withmethylene chloride (500 ml.) and twice with methylene chloride (200ml.), the extracts were combined. The combined extracts were washed witha saturated aqueous solution of sodium chloride, and adjusted to pH 6.5by adding water (800 ml.) and sodium bicarbonate. Methylene chloridelayer was separated, washed with an aqueous solution of sodium chlorideand dried over magnesium sulfate. The solvent was distilled off to giveethyl 2-methoxyimino-4-chloroacetoacetate (syn isomer) (559 g.).

I.R. spectrum (Film) 1735, 1705 cm⁻¹

PREPARATION 7

(1) A mixture of ethyl 2-hydroxyimino-4-bromoacetoacetate (a mixture ofsyn and anti isomers) (22.0 g.), thioacetamido (7.5 g.) and benzene (100ml.) was refluxed for 3 hours. After cooling triethylamine (10 g.) wasadded thereto and the mixture was stirred for 1 hour. An insolublematerial was filtered off and the filtrate was concentrated underreduced pressure to give ethyl2-hydroxyimino-2-(2-methyl-1,3-thiazol-4-yl)acetate (a mixture of synand anti isomers) (8.6 g.). This substance was subjected to columnchromatography on silica gel (80 g.) using benzene as developingsolvent. Firstly the eluate containing anti isomer was eluted, collectedand concentrated to give ethyl2-hydroxyimino-2-(2-methyl-1,3-thiazol-4-yl)acetate (anti isomer) (2.5g.), mp 90° to 92° C.

I.R. spectrum (Nujol) 1720 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 12.55 (1H, s), 8.25 (1H, s), 4.27(2H, q, J=7 Hz), 2.63 (3H, s), 1.25 (3H, t, J=7 Hz).

After the eluate containing anti isomer was eluted, the eluatecontaining syn isomer was eluted, collected and concentrated to giveethyl 2-hydroxyimino-2-(2-methyl-1,3-thiazol-4-yl)acetate (syn isomer)(0.5 g.), mp 134° to 136° C.

I.R. spectrum (Nujol) 1720 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 11.81 (1H, s), 7.81 (1H, s), 4.35(2H, q, J=7 Hz), 2.70 (3H, s), 1.30 (3H, t, J=7 Hz).

(2) Phenolphthalein indicator (3 drops) was added to a solution ofhydroxylamine hydrochloride (4.2 g.) in dry methanol (60 ml.). To thesolution was dropwise added with stirring at ambient temperature 1Nmethanol solution of sodium methoxide (60 ml.) until the color of thesolution was changed to purplish red. Hydroxylamine hydrochloride wasadded thereto by small portions until the solution was changed tocolorless solution. The mixture was stirred for 30 minutes at ambienttemperature. After precipitating sodium chloride was filtered off,2-(2-mesylamino-1,3-thiazol-4-yl)glyoxylic acid (12.5 g.) was added tothe filtrate and the mixture was refluxed with stirring for 1.5 hours.The reaction mixture was cooled to precipitate crystals. The crystalswere collected by filtration and dried to give crude2-hydroxyimino-2-(2-mesylamino-1,3-thiazol-4-yl)acetic acid (a mixtureof syn and anti isomers) (5.5 g.). The filtrate was concentrated to thevolume of 1/4 and ether was added thereto. Precipitating crystals werecollected by filtration, washed with ether and dried to give the samecompound (8.78 g.). Total yield (14.3 g.). (3) A mixture of ethyl2-hydroxyimino-4-bromoacetoacetate (a mixture of syn and anti isomers)(2.4 g) and thiourea (0.76 g) in ethanol (15 ml) was stirred for 1 hourat 60° C. Ethanol was distilled off under reduced pressure and water wasadded to the residue. The resultant mixture was adjusted to pH 1.0 andwashed with ethyl acetate. The aqueous layer was adjusted to pH 4.5 withtriethylamine and extracted with ethyl acetate. The extract was washedwith water and a saturated sodium chloride aqueous solution and driedover magnesium sulfate. The solvent was distilled off under reducedpressure and the residue was subjected to column chromatography onsilica gel using a mixture of ethyl acetate and benzene (1:3) asdeveloping solvent. The eluates containing syn isomer were collected andconcentrated to give ethyl2-hydroxyimino-2-(2-amino-1,3-thiazol-4-yl)acetate (syn isomer) (0.3 g).

I.R. spectrum (Nujol) 3450, 3300, 3200, 1725, 1620 cm⁻¹

N.M.R. spectrum (CDCl₃, δ) ppm: 7.65 (1H, s), 5.33 (2H, broad s), 4.40(2H, q, J=7.5 Hz), 1.38 (3H, t, J=7.5 Hz).

After the eluates containing syn isomers were collected, the eluatescontaining a mixture of syn and anti isomers were collected andconcentrated to give ethyl2-hydroxyimino-2-(2-amino-1,3-thiazol-4-yl)acetate (a mixture of syn andanti isomers) (0.3 g.).

I.R. spectrum (Nujol) 3400, 3300, 3200, 1715, 1620 cm⁻¹

N.M.R. spectrum (d6-DMSO, δ) ppm: 12.42 (1H, broad s), 11.55 (1H, s),7.52 (1H, s), 7.12 (4H, broad s), 6.83 (1H, s), 4.23 (4H, m), 1.26 (6H,m).

(4) A solution of ethyl2-hydroxyimino-2-(2-amino-1,3-thiazol-4-yl)acetate (a mixture of syn andanti isomers) (1.1 g) in an 1N aqueous solution of sodium hydroxide (15ml) was allowed to stand for 2 hours at ambient temperature. Thereaction mixture was adjusted to pH 3.5 with 10% hydrochloric acid andprecipitating crystals were collected by filtration, washed with acetoneand dried to give 2-hydroxyimino-2-(2-amino-1,3-thiazol-4-yl)acetic acid(a mixture of syn and anti isomers) (0.52 g), mp 184° to 186° C. (dec.).

I.R. spectrum (Nujol) 3200, 1670, 1530 cm⁻¹

PREPARATION 8

(1) Thioacetamide (3.8 g.) was added to a solution of ethyl2-methoxyimino-4-bromoacetoacetate (a mixture of syn and anti isomers)(12.6 g.) in ethanol (50 ml.) and the mixture was stirred for 5 hours at50° C. Ethanol was distilled off under reduced pressure and water wasadded to the residue. The resulting mixture was extracted with ethylacetate. The extract was in turn washed with water, a sodium bicarbonateaqueous solution and a saturated sodium chloride aqueous solution anddried over magnesium sulfate. The solvent was distilled off underreduced pressure to give ethyl2-methoxyimino-2-(2-methyl-1,3-thiazol-4-yl)acetate (a mixture of synand anti isomers) (9.0 g.).

(2) A mixture of ethyl 2-methoxyimino-4-bromoacetoacetate (a mixture ofsyn and anti isomers) (7.6 g.), O-ethyl thiocarbamate (3.0 g.) anddimethylacetamide (5 ml.) was stirred for 3 hours at 50° C. Ethylacetate (50 ml.) was added to the reaction mixture and the resultingmixture was washed with water and with a saturated sodium chlorideaqueous solution and dried over magnesium sulfate. Ethyl acetate wasdistilled off to give crystalline residue. The residue was washed withdiisopropyl ether to give ethyl2-methoxyimino-2-(2-oxo-2,3-dihydro-1,3-thiazol-4-yl)acetate (synisomer) (2.35 g.).

I.R. spectrum (Nujol) 3200, 1735, 1680, 1650 cm⁻¹

N.M.R. spectrum (CDCl₃, δ) ppm: 9.13 (1H, broad s), 6.37 (1H, s), 4.40(2H, q, J=6 Hz), 4.01 (3H, s), 1.38 (3H, t, J=6 Hz).

The mother liquor of diisopropyl ether was concentrated and the residuewas subjected to column chromatography on silica gel (70 g.) using amixture of benzene and ethyl acetate (9:1) as developing solvent. Theeluate containing syn isomer was collected and concentrated to furthergive the above obtained syn isomer (0.65 g.). Total yield (3.0 g.).Thereafter a mixture of benzene and ethyl acetate (5:1) was used asdeveloping solvent. The eluate containing anti isomer was collected andconcentrated to give ethyl2-methoxyimino-2-(2-oxo-2,3-dihydro-1,3-thiazol-4-yl)acetate (antiisomer) (0.26 g.).

I.R. spectrum (Nujol) 3250, 3200, 1720, 1690 cm⁻¹

N.M.R. spectrum (CDCl₃, δ) ppm: 9.90 (1H, broad s), 7.30 (1H, s), 4.40(2H, q, J=6 Hz), 4.03 (3H, s), 1.38 (3H, t, J=6 Hz).

(3) A solution of ethyl 2-methoxyimino-4-bromoacetoacetate (a mixture ofsyn and anti isomers) (17.4 g.) and thiourea (5.4 g.) in ethanol (100ml.) was refluxed for 4 hours. The reaction mixture was allowed to standand cooled in refrigerator to precipitate crystals. The crystals werecollected by filtration, washed with ethanol and dried to give ethyl2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetate hydrobromide (antiisomer) (9.5 g.). The filtrate and the washings were put together andconcentrated under reduced pressure. Water (100 ml.) was added to theresidue and the mixture was washed with ether. The aqueous layer wasalkalized with a 28% aqueous solution of ammonia and extracted withethyl acetate. The extract was washed with water and a saturated sodiumchloride aqueous solution and dried over magnesium sulfate. The solventwas distilled off under reduced pressure to give crystalline substanceof ethyl 2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetate (syn isomer)(5.2 g.).

I.R. spectrum (Nujol) 3400, 3300, 3150, 1725, 1630, 1559 cm⁻¹

N.M.R. spectrum (CDCl₃, δ) ppm: 6.72 (1H, s), 5.91 (2H, broad s), 4.38(2H, q, J=7 Hz), 4.03 (3H, s), 1.38 (3H, t, J=7 Hz).

The above obtained ethyl2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetate hydrobromide (antiisomer) (9.5 g.) was suspended in ethyl acetate (200 ml.) andtriethylamine (4.0 g.) was added thereto. After stirring for 1 hour atambient temperature, an insoluble material was filtered off and thefiltrate was concentrated under reduced pressure to give crystallinesubstance of ethyl 2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetate(anti isomer) (6.15 g.).

I.R. spectrum (Nujol) 3450, 3250, 3150, 1730, 1620 cm⁻¹

N.M.R. spectrum (CDCl₃, δ) ppm: 7.50 (1H, s), 5.60 (2H, broad s), 4.35(2H, q, J=7 Hz), 4.08 (3H, s), 1.33 (3H, t, J=7 Hz).

(4) Phenolphthalein indicator (3 drops) was added to a solution ofO-methyl-hydroxylamine hydrochloride (1.25 g.) in dry methanol (15 ml.).To the solution was dropwise added with stirring at ambient temperature1N methanol solution of sodium methoxide (13 ml.) until the color of thesolution was changed to purplish red. O-Methylhydroxylaminehydrochloride was added thereto by small portions until the solution waschanged to colorless solution. The mixture was stirred for 30 minutes atambient temperature. After precipitating sodium chloride was filteredoff, ethyl 2-(2-mesylamino-1,3-thiazol-4-yl)glyoxylate (3.8 g.) wasadded to the filtrate and the mixture was refluxed with stirring for 2hours. After methanol was distilled off, the residue was dissolved inethyl acetate. An insoluble material was filtered off and the filtratewas concentrated. The residue was subjected to column chromatography onsilica gel using a mixture of benzene and ethyl acetate (9:1) asdeveloping solvent. The eluate containing syn isomer was collected andconcentrated to give ethyl2-methoxyimino-2-(2-mesylamino-1,3-thiazol-4-yl)acetate (syn isomer)(2.8 g.).

I.R. spectrum (Nujol) 1725 cm⁻¹

N.M.R. spectrum (CDCl₃, δ) ppm: 6.76 (1H, s), 4.44 (2H, q, J=7 Hz), 4.04(3H, s), 3.04 (3H, s), 1.37 (3H, t, J=7 Hz).

(5) Pulverized potassium carbonate (0.33 g.) was suspended in a solutionof ethyl 2-hydroxyimino-2-(2-methyl-1,3-thiazol-4-yl)acetate (synisomer) (0.5 g.) in acetone (20 ml.). A solution of dimethyl sulfate(0.3 g.) in acetone (5 ml.) was dropwise added thereto with stirring at40° to 45° C. After stirring for 2 hours at the same temperature, aninsoluble material was filtered off. The filtrate was concentrated andwater was added to the residue. The resulting mixture was extracted withethyl acetate. The extract was in turn washed with water, a sodiumbicarbonate aqueous solution and a saturated sodium chloride aqueoussolution and dried over magnesium sulfate. The solvent was distilled offunder reduced pressure to give pale yellow oil of ethyl2-methoxyimino-2-(2-methyl-1,3-thiazol-4-yl)acetate (syn isomer) (0.5g.).

I.R. spectrum (Film) 1740, 1710, 1595 cm⁻¹

N.M.R. spectrum (CDCl₃, δ) ppm: 7.40 (1H, s), 4.25 (2H, q, J=7 Hz), 4.03(3H, s), 2.73 (3H, s), 1.38 (3H, t, J=7 Hz).

(6) 2-Hydroxyimino-2-(2-mesylamino-1,3-thiazol-4-yl)acetic acid (amixture of syn and anti isomers) (14.3 g.) obtained in Preparation 7-2)was suspended in dry acetone (300 ml.). To the suspension were addedpotassium carbonate (22.8 g.) and dimethy sulfate (20.8 g.). The mixturewas refluxed with stirring for 9 hours. Acetone was distilled off fromthe reaction mixture and water was added to the residue. The resultingmixture was extracted with ethyl acetate. The extract was washed with asodium chloride aqueous solution and dried over magnesium sulfate. Thesolvent was distilled off to give oil (13 g.). The oil was subjected tocolumn chromatography on silica gel using a mixture of benzene and ethylacetate (9:1) as developing solvent. Firstly the eluate containing antiisomer was eluted, collected and concentrated. The residual oil (2.4 g.)was triturated under cooling to crystallize. The crystals were collectedby filtration by adding petroleum ether to give methyl2-methoxyimino-2-(2-mesylimino-3-methyl-2,3-dihydro-1,3-thiazol-4-yl)acetate(anti isomer) (2.1 g.).

I.R. spectrum (Nujol) 1740 cm⁻¹

N.M.R. spectrum (CDCl₃, δ) ppm: 7.90 (1H, s), 4.10 (3H, s), 3.90 (3H,s), 3.47 (3H, s), 3.07 (3H, s).

After the eluate containing anti isomer was eluted, the eluatecontaining syn isomer was eluted, collected and concentrated to givecrystals of methyl2-methoxyimino-2-(2-mesylimino-3-methyl-2,3-dihydro-1,3-thiazol-4-yl)acetate(syn isomer) (5.5 g.).

I.R. spectrum (Nujol) 1740 cm⁻¹

N.M.R. spectrum (CDCl₃, δ) ppm: 6.72 (1H, s), 4.05 (3H, s), 3.92 (3H,s), 3.72 (3H, s), 3.01 (3H, s).

(7) The following compound was obtained according to a similar manner tothat of Preparation 8-4).

Ethyl 2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetate (syn isomer).

I.R. spectrum (Nujol) 3400, 3300, 3150, 1725, 1630, 1559 cm⁻¹

N.M.R. spectrum (CDCl₃, δ) ppm: 6.72 (1H, s), 5.91 (2H, broad s), 4.38(2H, q, J=7 Hz), 4.03 (3H, s), 1.38 (3H, t, J=7 Hz).

(8) A mixture of acetic anhydride (6.1 g) and formic acid (2.8 g) wasstirred for 2 hours at 50° C. The resulting mixture was cooled and ethyl2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetate (syn isomer) (4.6 g)was added thereto at 15° C. After the mixture was stirred for 3.5 hoursat ambient temperature, cooled water (100 ml) was added thereto. Theresulting mixture was extracted with ethyl acetate (200 ml). The extractwas washed with water and then with a saturated aqueous solution ofsodium bicarbonate until the washing was changed to weakly alkalinesolution. The extract was further washed with a saturated aqueoussolution of sodium chloride and dried over magnesium sulfate. Thesolvent was distilled off and the residue was washed with diisopropylether, collected by filtration and dried to give ethyl2-methoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acetate (syn isomer)(4.22 g), mp 122° to 124° C. (dec.).

I.R. spectrum (Nujol) 3150, 1728, 1700 cm⁻¹

N.M.R. spectrum (CDCl₃, δ) ppm: 12.58 (1H, broad s), 8.95 (1H, s), 7.17(1H, s), 4.42 (2H, q, J=8 Hz), 4.00 (3H, s), 1.37 (3H, t, J=8 Hz).

(9) Pyridine (3 g.) was added to a solution of ethyl2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetate (syn isomer) (6.5 g.)in a mixture of ethyl acetate (60 ml.) and dimethylformamide (20 ml.).To the solution was dropwise added with stirring at 4° C. ethylchloroformate (8 g.). After adding water (50 ml.) to the reactionmixture, the organic layer was separated, washed with water and thenwith a saturated aqueous solution of sodium chloride and dried overmagnesium sulfate. The solvent was distilled off under reduced pressure.The residue was subjected to column chromatography on silica gel (120g.) using a mixture of ether and petroleum ether (5:2) as an eluent togive ethyl2-methoxyimino-2-(2-ethoxycarbonylamino-1,3-thiazol-4-yl)acetate (synisomer) (5.4 g.).

N.M.R. spectrum (CDCl₃, δ) ppm: 9.36 (1H, broad s), 7.10 (1H, s),4.00-4.66 (4H, m), 4.00 (3H, s), 1.20-1.60 (6H, m).

(10) Ethyl 2-methoxyimino-4-chloroacetoacetate (syn isomer) (50 g.) wasadded over 3 minutes with stirring at ambient temperature to a solutionof thiourea (18.4 g.) and sodium acetate (19.8 g.) in a mixture ofmethanol (250 ml.) and water (250 ml.). After stirring for 35 minutes at40° C., the reaction mixture was cooled with ice and adjusted to pH 6.3with a saturated aqueous solution of sodium bicarbonate. After stirringfor 30 minutes at the same temperature, precipitates were collected byfiltration, washed with water (200 ml.) and then with diisopropyl ether(100 ml.), and dried to give colorless crystals of ethyl2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetate (syn isomer) (37.8g.), mp 161° to 162° C.

I.R. spectrum (Nujol) 3400, 3300, 3150, 1725, 1630, 1559 cm⁻¹

N.M.R. spectrum (CDCl₃, δ) ppm: 6.72 (1H, s), 5.91 (2H, broad s), 4.38(2H, q, J=7 Hz), 4.03 (3H, s), 1.38 (3H, t, J=7 Hz).

(11) Ethyl 2-hydroxyimino-2-(2-methyl-1,3-thiazol-4-yl)acetate (antiisomer) (0.3 g.) and dimethyl sulfate (0.18 g.) were reacted accordingto a similar manner to that of Preparation (8-5) to give pale yellow oilof ethyl 2-methoxyimino-2-(2-methyl-1,3-thiazol-4-yl)acetate (antiisomer) (0.27 g.).

I.R. spectrum (Film) 1750, 1605 cm⁻¹

N.M.R. spectrum (CDCl₃, δ) ppm: 8.07 (1H, s), 4.41 (2H, q, J=7 Hz), 4.13(3H, s), 2.75 (3H, s), 1.40 (3H, t, J=7 Hz).

(12) The following compound was obtained according to a similar mannerto that of Preparation 8-8).

ethyl 2-methoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acetate (antiisomer), mp 96° to 99° C. (dec.).

I.R. spectrum (Nujol) 3150, 1740, 1650, 1600 cm⁻¹

N.M.R. spectrum (CDCl₃, δ) ppm: 11.20 (1H, broad s), 8.60 (1H, s), 7.90(1H, s), 4.32 (2H, q, J=8 Hz), 4.13 (3H, s), 1.32 (3H, t, J=8 Hz).

PREPARATION 9

(1) Ethanol (10 ml.) was added to a suspension of ethyl2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetate (syn isomer) (2.2 g.)in a 1N aqueous solution of sodium hydroxide (12 ml.) and the mixturewas stirred for 15 hours at ambient temperature. The reaction mixturewas adjusted to pH 7.0 with 10% hydrochloric acid and ethanol wasdistilled off under reduced pressure. The residual aqueous solution waswashed with ethyl acetate, adjusted to pH 2.8 with 10% hydrochloric acidand stirred under ice-cooling to precipitate crystals. The crystals werecollected by filtration, washed with acetone and recrystallized fromethanol to give colorless needles of2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetic acid (syn isomer) (1.1g.).

I.R. spectrum (Nujol) 3150, 1670, 1610, 1585 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 7.20 (2H, broad s), 6.85 (1H, s),3.83 (3H, s).

(2) 1N-Aqueous solution of sodium hydroxide (1.5 ml.) was added to asolution of ethyl 2-methoxyimino-2-(2-methyl-1,3-thiazol-4-yl)acetate(syn isomer) (0.3 g.) in ethanol (5 ml.) and the resulting mixture wasstirred for 2 hours at 40° C. The reaction mixture was adjusted to pH7.0 with 10% hydrochloric acid, concentrated under reduced pressure,adjusted to pH 1.5 with 10% hydrochloric acid and extracted with ethylacetate. The extract was washed with water and a saturated sodiumchloride aqueous solution and dried over magnesium sulfate. The solventwas distilled off to give crystalline substance of2-methoxyimino-2-(2-methyl-1,3-thiazol-4-yl)acetic acid (syn isomer)(0.14 g.).

I.R. spectrum (Nujol) 1730 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 7.80 (1H, s), 3.85 (3H, s), 2.62 (3H,s).

(3) The following compounds were obtained according to similar mannersto those of Preparation (9-1) to (9-2).

(1) 2-Methoxyimino-2-(2-oxo-2,3-dihydro-1,3-thiazol-4-yl)acetic acid(syn isomer).

I.R. spectrum (Nujol) 3250, 1710, 1650 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 10.61 (1H, broad s), 6.73 (1H, s),3.95 (3H, s).

(2) 2-Methoxyimino-2-(2-mesylamino-1,3-thiazol-4-yl)acetic acid (synisomer).

I.R. spectrum (Nujol) 3150, 1720 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 7.17 (1H, s), 3.93 (3H, s), 3.02 (3H,s).

(3)2-Methoxyimino-2-(2-mesylimino-3-methyl-2,3-dihydro-1,3-thiazol-4-yl)aceticacid (syn isomer).

I.R. spectrum (Nujol) 1730 cm⁻¹

(4) 2-Methoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acetic acid (synisomer), mp 152° C. (dec.).

I.R. spectrum (Nujol) 3200, 2800-2100, 1950, 1600 cm⁻¹

N.M.R. spectrum (d6-DMSO, δ) ppm: 8.60 (1H, s), 7.62 (1H, s), 3.98 (1H,s).

(5) 2-Methoxyimino-2-(2-ethoxycarbonylamino-1,3-thiazol-4-yl)acetic acid(syn isomer).

I.R. spectrum (Nujol) 3200, 1730, 1710, 1690, 1570 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 12.16 (1H, broad s), 7.50 (1H, s),7.20 (1H, broad s), 4.25 (2H, q, J=7 Hz), 3.93 (3H, s), 1.25 (3H, t, J=7Hz).

(4) Pyridine (5 ml.) was added to a suspension of2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetic acid (syn isomer) (2.0g.) in ethyl acetate (20 ml.). A solution ofbis(2,2,2-trifluoroacetic)anhydride (2.5 g.) in ethyl acetate (3 ml.)was dropwise added thereto with stirring at 5° to 7° C. and the mixturewas stirred for 30 minutes at 3° to 5° C. Water (30 ml.) was added tothe reaction mixture and the ethyl acetate layer was separated. Theaqueous layer was further extracted with ethyl acetate and two ethylacetate layers were combined together, washed with water and a saturatedsodium chloride aqueous solution and dried over magnesium sulfate. Thesolvent was distilled off under reduced pressure to give2-methoxyimino-2-[2-(2,2,2-trifluoroacetamido)-1,3-thiazol-4-yl]aceticacid (syn isomer) (0.72 g.).

I.R. spectrum (Nujol) 1725, 1590 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 7.68 (1H, s), 3.91 (3H, s).

(5) The following compound was obtained according to a similar manner tothat of Preparation 9-4).

2-Methoxyimino-2-(2-acetamido-1,3-thiazol-4-yl)acetic acid (syn isomer),mp 184° to 185° C. (dec.).

I.R. spectrum (Nujol) 3200, 3050, 1695, 1600 cm⁻¹

(6) Phenolphthalein indicator (3 drops) was added to a solution ofO-allyl-hydroxylamine hydrochloride (0.84 g.) in dry methanol (10 ml.).To the solution was dropwise added with stirring at ambient temperature1N methanol solution of sodium methoxide (6 ml.) until the color of thesolution was changed to pale pink. O-Allylhydroxylamine hydrochloridewas added thereto by small portions until the solution was changed tocolorless solution. The mixture was stirred for 30 minutes at ambienttemperature. After precipitating sodium chloride was filtered off,2-(2-t-pentyloxycarbonylamino-1,3-thiazol-4-yl)glyoxylic acid (2.0 g.)was added to the filtrate and the mixture was stirred for 1 hour atambient temperature. After methanol was distilled off at lowtemperature, the residue was dissolved in an 1N aqueous solution ofsodium hydroxide. The solution was washed with ether and ethyl acetatewas added thereto. The mixture was adjusted to pH 1.5 with phosphoricacid and extracted with ethyl acetate. The extract was washed with asodium chloride aqueous solution and dried over magnesium sulfate. Ethylacetate was distilled off and the residue was washed with diisopropylether, collected by filtration and dried to give2-allyloxyimino-2-(2-t-pentyloxycarbonylamino-1,3-thiazol-4-yl)aceticacid (syn isomer) (1.62 g.).

I.R. spectrum (Nujol) 3200, 1712 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 7.40 (1H, s), 6.24-5.76 (1H, m), 5.26(2H, dd, J=9, 10 Hz), 4.65 (2H, d, J=5 Hz), 1.78 (2H, q, J=8 Hz), 1.44(6H, s), 0.88 (3H, t, J=8 Hz).

(7) The following compounds were obtained according to a similar mannerto that of Preparation 9-6).

(1) 2-Methoxyimino-2-(2-t-pentyloxycarbonylamino-1,3-thiazol-4-yl)aceticacid (syn isomer).

I.R. spectrum (Nujol) 3200, 1712 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 7.40 (1H, s), 3.88 (3H, s), 1.77 (2H,q, J=8 Hz), 1.44 (6H, s), 0.88 (3H, t, J=8 Hz).

(2) 2-Allyloxyimino-2-(2-mesylamino-1,3-thiazol-4-yl)acetic acid (synisomer).

I.R. spectrum (Nujol) 3150, 1710, 1605 cm⁻¹

(3) 2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetic acid (syn isomer).

I.R. spectrum (Nujol) 3150, 1670, 1610, 1585 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 7.20 (2H, broad s), 6.85 (1H, s),3.83 (3H, s).

(8) Ethyl 2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetatehydrobromide (anti isomer) (15.5 g.) was dissolved in a solution ofsodium hydroxide (4.4 g.) in water (150 ml.) and the resulting solutionwas stirred for 1 hour at ambient temperature. An insoluble material wasfiltered off and the filtrate was adjusted to pH 5.0 to precipitatecrystals. The crystals were collected by filtration and dried to give2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetic acid (anti isomer)(8.0 g.).

I.R. spectrum (Nujol) 3150, 1655, 1595, 1550 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 7.53 (1H, s), 7.23 (2H, broad s),3.99 (3H, s).

(9) The following compounds were obtained according to similar manner tothat of Preparation 9-8).

(1) 2-Methoxyimino-2-(2-methyl-1,3-thiazol-4-yl)acetic acid (antiisomer)

I.R. spectrum (Nujol) 1730, 1590 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 8.10 (1H, s), 4.00 (3H, s), 2.65 (3H,s).

(2)2-Methoxyimino-2-(2-mesylimino-3-methyl-2,3-dihydro-1,3-thiazol-4-yl)aceticacid (anti isomer).

I.R. spectrum (Nujol) 1730 cm⁻¹

(3) 2-Methoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acetic acid (antiisomer), mp 156° to 158° C. (dec.).

I.R. spectrum (Nujol) 3200, 2700-2100, 1690, 1590, 1560 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 8.05 (1H, s), 4.02 (3H, s).

What we claim is:
 1. Syn-isomer of 3,7-disubstituted-3-cephem-4-carboxylic acid compounds of the formula: ##STR24## whereinR⁴ is thiadiazolylthiomethyl, and pharmaceutically acceptable saltsthereof.
 2. The compound7-[2-methoxyimino-2-(2amino-1,3-thiazol-4-yl)-acetamido]-3-(1,3,4-thiadiazol-2-yl)-thiomethyl-3-cephem-4-carboxylicacid (syn isomer).